Regio- and Enantioselective Intramolecular Amide Carbene Insertion into Primary C-H Bonds Using Ru(II)-Pheox Catalyst

Article abstract of DOI:10.1021/acs.joc.8b03044

We have established a method for the highly regio- and enantioselective functionalization of tert-butyl groups via intramolecular amide carbene insertion into C-H bonds, yielding γ-lactams with 91% ee in up to 99% yield. This reaction uses a ruthenium(II) phenyl oxazoline (Ru(II)-Pheox) complex. The catalytic intramolecular carbene transfer reaction to the primary C-H bond proceeds rapidly and selectively compared to that with secondary C-H, benzylic secondary C-H, tert-C-H, or sp²C-H bonds in the presence of 1 mol % Ru(II)-Pheox catalyst. This is the first example of a catalytic carbenoid insertion into an unactivated tert-butyl group with enantiocontrol at the carbenoid carbon.

Full text of DOI:10.1021/acs.joc.8b03044

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Article
Regio- and Enantioselective Intramolecular Amide Carbene
Insertion into Primary C#H Bonds using Ru(II)-Pheox Catalyst
Yoko Nakagawa, Soda Chanthamath, Yumeng Liang, Kazutaka Shibatomi, and Seiji Iwasa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03044 • Publication Date (Web): 31 Jan 2019
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Page 1 of 14
The Journal of Organic Chemistry
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Regio- and Enantioselective Intramolecular Amide Carbene
Insertion into Primary C‒H Bonds using Ru(II)-Pheox Catalyst
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Yoko Nakagawa, Soda Chanthamath*, Yumeng Liang, Kazutaka Shibatomi, and Seiji Iwasa*
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Tempaku-cho, Toyohashi, Aichi,
Japan 441-8580.
Supporting Information Placeholder
25 mol% of a (p-cymene)ruthenium(II) complex to give γ-lactam
ABSTRACT: We have established a method for the highly
5 (Scheme 1, a).6, 7 This report was the first example of the highly
regio- and enantioselective functionalization of tert-butyl groups
regioselective functionalization of primary C‒H bonds, although
benzylic secondary C‒H bonds and the sp2C‒H bonds of the
phenyl group are usually more reactive. However,
enantioselective functionalization of unactivated primary C‒H
bond to give optically active γ-lactam 6 had not been reported
(Scheme 1, a).
via intramolecular amide carbene insertion to C‒H bonds,
yielding γ-lactams with 91% ee in up to 99% yield. This reaction
uses a ruthenium(II) phenyl oxazoline (Ru(II)-Pheox) complex.
The catalytic intramolecular carbene transfer reaction to the
primary C–H bond proceeds rapidly and selectively compared to
that with secondary C‒H, benzylic secondary C‒H, tert-C‒H, or
sp2C‒H bonds in the presence of 1 mol% Ru(II)-Pheox catalyst.
This is the first example of a catalytic carbenoid insertion into an
unactivated tert-butyl group with enantiocontrol at the carbenoid
carbon.
Development of highly regio- and enantioselective C‒H
functionalization reactions of a wide range of substrates would
present a paradigm shift from the traditional functional group
transformation chemistry in the field of organic synthesis.
R
O
H
N2
e

c
a
O
b
INTRODUCTION
N
H
H
R
d
a
1° CH
n
N
Transition metal-catalyzed alkane C‒H functionalization has
attracted much attention because of the dynamic molecular
transformation from an initial skeleton to more complicated and
functionalized organic compounds.1 Carbenes are known to be a
highly reactive intermediate and are candidates for the activation
of unactivated primary C‒H bonds if the reaction can be
controlled. The reactivity of carbene insertion into C‒H bond
generally depends on the bond dissociation energy; thus, C–H
bonds react with reactive intermediates in the order tertiary >
secondary > primary. Therefore, the selective carbene insertion of
unactivated primary C‒H bonds remains a challenging research
theme.2 Recently, we reported highly efficient transition metal
carbene transfer catalysts and their applications for the synthesis
of optically active cyclopropane derivatives in high yields with
high stereoselectivities.3 Furthermore, we demonstrated transition
metal catalyzed N‒H and Si‒H insertion reactions of carbenes to
construct N‒C and Si‒C bonds having chiral centers at the carbon
and silicon atoms.4 In the course of our studies, we identified a
carbene transfer reaction to the unactivated methyl C–H bond of
the tert-butyl group when using a ruthenium(II) phenyl oxazoline
complex (Ru(II)-Pheox, Figure 1).
H
n
H
5
6
(R = H), (R = Me)
1
b or c
O
R
Amide carbene precursor
H

(n = 0, 1, 2)
N
n
e
d
2
O
O
R
H
R
R
O

N

N
N
n
n
n
4
3
Scheme 1. Intramolecular C‒H insertion reactions using transition
metal catalysts.
PF6
 Relatively inexpensive complex
Diazoacetamide 1 has an sp2C‒H bond in the phenyl group, and
its secondary and primary C‒H bonds have been selected for the
study of the regio- and stereoselective C–H functionalization by
carbene transfer. Diazoacetamide 1 yields mainly β-lactam 2 via
an intramolecular carbene insertion reaction into the secondary
C‒H bond, seven-membered ring-fused γ-lactam 3 as a minor
product via cyclopropanation onto the aromatic ring, followed by
Büchner ring expansion, and lactams 4 via carbene insertion
reaction into sp2C‒H bond of phenyl group (Scheme 1, b, c, d and
e).5 In 2012, Lo and co-workers reported intramolecular carbene
insertions into primary C‒H bonds of the tert-butyl group using
O
 Easy access and simple structure
 Tunable chiral environment
 Tunable properties of central metal
 Various asymmetric carbene
transfer reactions
Ru
(NCCH3)4
Ru(II)-Pheox catalyst
N
Ph
Figure 1. Ru(II)-Pheox catalyst and its properties.
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RESULT AND DISCUSSION
1
rac-
Ru(II)-Pheox
(1 mol%)
O
O
First, the intramolecular C‒H insertion reaction of diazoamide 7
including the sp2 C‒H bonds of the aromatic ring, benzylic,
secondary, and primary C‒H bonds was investigated in the
presence of the rac-Ru(II)-Pheox catalyst. The results are
summarized in Table 1. The intramolecular amide carbene
transfer reaction of diazoamide 7a to secondary and primary C‒H
bonds proceeded rapidly at room temperature in dichloromethane
in the presence of 1 mol% Ru(II)-Pheox catalyst to give γ-lactam
8a in moderate yield (51% yield) and β-lactam 9a in 43% yield
(Table 1, entry 1).γ-Lactam 8a was produced by the carbene
insertion reaction into the unactivated primary C‒H bond of tert-
butyl group, and this carbene insertion reaction into a primary
C‒H bond is an extremely rare reaction. β-Lactam 9a was
obtained from the carbene insertion reaction into the secondary
C‒H bond. Subsequently, the electronic effect of the benzene ring
was examined for the C–H insertion reaction with an amide
carbene (Table 1, entries 2–5). When electron withdrawing groups
such as Cl and NO2 were substituted at the para-position of the
benzene ring, the regioselectivity ratio for insertion into the
primary C‒H bond was increased, giving the desired γ-lactams in
moderate to high yields via the catalytic functionalization of the
tert-butyl group (Table 1, entries 2 and 3). Diazoamide 7d, which
has a methyl group, gave almost the same result as 7a (Table 1,
entry 4). The regioselectivity of the carbene transfer reaction for
7e, which has a methoxy group as an electron donating group,
2
3
4
5
6
7
8
9
N2
N
O
N
(1)
+
RT, CH2Cl2,
10 min
N
11
12
13
60% yielda
17% yielda
rac-
Ru(II)-Pheox
(1 mol%)
O
O
N2
N
(2)
N
RT, CH2Cl2,
20 min
15
81% yield
14
Scheme 2. Intramolecular C‒H insertion reaction of various N-
substituted α-diazoacetamides using the rac-Ru(II)-Pheox
catalyst. a Determined by 1H NMR.
10
11
12
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16
17
18
19
20
21
22
23
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54
55
56
57
58
59
60
dramatically changed, giving a seven-membered ring-fused γ-
lactam 10e, via cyclopropanation onto the aromatic moiety,
followed by Büchner ring expansion, in 94% yield (Table, 1, entry
5).This regioselectivity, as for C‒H insertion by an amide
carbene, was found to be sensitive to the electronic effects of the
phenyl group, and the highest yield of γ-lactams via insertion into
the primary C‒H bond was 83% (Table 1, entry 3). Next, we
investigated carbene transfer reactions using various
diazoacetamides that have long carbon side chains such as –
CH2CH2Ph and –CH2CH2CH2Ph (7f–7i). As a result, the insertion
reaction into secondary C‒H bonds was decreased, and the
insertion reaction into primary C‒H bond proceeded smoothly and
selectively in high yields of up to 99% yield (Table 1, entries 6
and 9).8 In the case of substrates, 7g and 7i having an electron
donating group, the desired functionalization of the tert-butyl
group proceeded selectively in high yield to give 8g and 8i in 75%
and 96% yield because of the C–H bond activity and probability
of the reaction site (Table 1, entries 8 and 10).
Table 1. Intramolecular C‒H insertion reaction of α-
diazoacetamides using racemic Ru(II)-Pheox catalyst.
R
O
rac-Ru(II)-Pheox
N2
(1 mol%)
N
n
RT, CH2Cl2
Furthermore, carbene transfer reactions using various N-
substituted diazoacetamides having N-isopropyl (11) and tert-
pentyl (14) groups were investigated (Scheme 2). γ-Lactam 12, -
lactams 13 and 15 were obtained respectively via carbene
insertion reactions into the secondary C‒H bond.These results
suggested that the C‒H insertion reaction of dizoacetamide is
sensitive of the N-substitutuents and may depend on the relative
stability and conformational environment of metal–carbene
reactive intermediates.
7a-7i
R
O
O
O
R
N
+
+
n
R
N
N
n
n
8a-8i
9a-9i
10a-10i
total
yield
[%]a
diazoamide 7
R
time
[min]
yield [%]a
entry
Thus, we examined the C–H insertion reaction using only dialkyl
substituted diazoacetamides 16 and 18 in the presence of Ru(II)-
Pheox (Scheme 3, (1) and (2)). Surprisingly, simple
diazoacetamide 16 afforded γ-lactam 17 as the sole product in
90% yield via the functionalization of the tert-butyl group, and the
reaction was also completed in the presence of 1 mol% of Ru(II)-
Pheox within 1 min at room temperature.
n
8
9
10
1
2
H (7a)
0
0
0
0
0
1
1
1
2
2
1
1
1
1
1
1
5
1
1
1
94
99
95
94
94
94
93
93
99
96
51
59
83
47
0
43
32
12
47
trace
8
Cl (7b)
NO2 (7c)
Me (7d)
OMe (7e)
H (7f)
3
0
rac-
Ru(II)-Pheox
(1 mol%)
O
O
4
trace
N2
N
N
(1)
5
trace 94
RT, CH2Cl2, 1 min
17
16
6
94 trace
93 trace
0
0
0
0
0
90% yield
rac-
Ru(II)-Pheox
(2 mol%)
O
O
7b
8
H (7f)
N2
O
N
N
N
(2)
(3)
+
OMe (7g)
H (7h)
75
99
96
18
0
RT, CH2Cl2, 20 h
19
20
67% yield
18
9
28% yield
rac-
Ru(II)-Pheox
(1 mol%)
O
10
OMe (7i)
0
N2
R
Dimerization only
N
H
RT, CH2Cl2, 1 h
a
b
Isolated yield. 0.1 mol% of rac-Ru(II)-Pheox catalyst was
R = Bn: 21, R = t-Bu: 22
used.
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Scheme 3. Intramolecular C‒H insertion reaction using various
Thus, p-MeO-Ru(II)-Pheox complex (cat. 4) was selected and
1
2
3
4
5
6
7
8
diazo compounds.
applied to develop asymmetric intramolecular C‒H insertion
reactions of α-diazoacetamides. The results of the p-MeO-Ru(II)-
Pheox (cat. 4) catalyzed C‒H insertion reaction of α-
diazoacetamides are shown in Table 3.
The carbene transfer reaction using diisopropyl diazoacetamide 18
afforded γ-lactam 19 in 28% yield, and the main product was β-
lactam 20 in 67% yield via a C‒H insertion reaction into the
tertiary C‒H bond of the isopropyl group (Scheme 3, (2)).5b On
the other hand, mono-substituted diazoacetamides 21 and 22 gave
only dimers of the diazoamide (Scheme 3, (3)). Furthermore, the
C‒H insertion reaction could not proceed when tert-butyl
diazoacetate was used, and the reaction gave only the
dimerization product.
Table 2. Catalyst and temperature effects on the asymmetric
intramolecular C‒H insertion reaction of α-diazoacetamides.
O
cat.
(5 mol%)
O
N2
9
N
N

T °C, CH2Cl2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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49
50
51
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58
59
60
23b
24b
In our previous research, computational chemical analysis of
Ru(II) ‐ Pheox catalyzed intramolecular cyclopropanation
reactions was performed by DFT calculation.3g These results gave
us the plausible reaction intermediate of Ru(II)-Pheox catalyzed
carbene insertion reaction into C–H bond (Figure 2). We expected
that the selectivity for the C–H insertion reaction by the amide
carbene is driven by the formation of different metal–carbene
complexes, arising from different conformations of the
diazoacetate molecule itself.
T
[°C]
time
[h]
yield
[%]a
ee
entry
cat.
solvent
[%]b
1
2
cat. 1 CH2Cl2
cat. 1 CH2Cl2
cat. 2 CH2Cl2
cat. 3 CH2Cl2
cat. 4 CH2Cl2
cat. 5 CH2Cl2
RT
0
3
77
72
65
38
67
41
75
9
75
84
78
77
87
82
76
65
70
77
24
3
3
RT
RT
RT
RT
RT
RT
RT
RT
4c
5
48
3
The Ru(II)-Pheox catalyzed carbene insertion reaction into a
primary C‒H bond may pass through metal–carbene transition
state I. This catalytic process allows asymmetric intramolecular
insertion into the unactivated primary C‒H bond because the fixed
intermediate can induce chirality by the presence of a chiral
ligand.
6
24
22
4
7
cat. 4
cat. 4
cat. 4
THF
8
MeOH
toluene
O
O
9
54
96
34
N
N
Ru
Ru
N
N
H
H
10
cat. 4 acetone
61
O
a
b
c
O
Isolated yield. Determined by chiral HPLC. 7 mol% of
catalyst was used.
I
II
R1
Figure 2. Plausible conformations of metal–carbene complexes of
diazoacetamide 16 for the activation of the primary C‒H bond of
tert-butyl and ethyl groups.
PF6
R2
cat
R1
H
R2
R3
cat. 1
H
H
H
H
H
H
H
H
R3
O
cat. 2 CF3
cat. 3 NO2
cat. 4 OMe
Ru
N
Therefore, we next investigated the Ru(II)-Pheox catalyzed
enantio- and regioselective functionalization of unactivated
primary C‒H bond with α-methyl diazoacetamide as an example
of a synthetic method with pharmaceutical applications. The
exploration of the functionalization of the C‒H bond of
diazoacetamide 23b was examined by the screening of various
chiral Ru(II)-Pheox catalysts (Table 2).
Ph
(NCCH3)4
cat. 5 OMe OMe OMe
cat. 15
The reaction of various α-substituted diazoacetamides 23a–23h
was investigated under the optimized reaction conditions (Table
3). Carbene insertion reaction proceeded into secondary C‒H
bond and disered γ-lactam was not provided (Table 3, entry 1).
Diazoacetamides having secondary C‒H bonds smoothly
provided the corresponding γ-lactams 24b‒24c and 24f‒24g via
insertion reaction into primary C‒H bond of tert-butyl group in
moderate to high yields with high enantioselectivities (Table 3,
entry 2, 3, 6 and 7). However, when diacceptor carbene precousor
23d was used for catalytic asymmetric carbene insertion reaction,
desired reaction into primary C‒H bond was not observed.
Corresponding γ-lactam was obtained in high yield via carbene
insertion reaction into secondary C‒H bond (Table 3, entry 4).
Diazoacetamide 23e could not give any product by Ru(II)-Pheox
catalyst under reflux condition (Table 3, entry 5). In contrast, the
regio- and enantioselective functionalization of the primary C‒H
bond of simple α-methyl diazoacetamide 23h proceeded in the
presence of 7 mol% of cat. 4, giving γ-lactam 24h in 70% yield
with 91% ee (Table 3, entry 8). These results indicate that the
Predictably, the desired enantio- and regioselective reactions
proceeded smoothly in the presence of chiral Ru(II)-Pheox
catalyst (cat. 1) at room temperature in dichloromethane, resulting
in γ-lactam 24b in 77% yield with 75% ee (Table 2, entry 1). The
enantioselectivity was improved to 84% ee at 0 °C; however, the
reactivity was decreased (Table 2, entry 2).
The reactivity of the C–H insertion reaction using the catalytic
reactivity of Ru(II)-Pheox complex can be tuned by choosing the
substituent on the aromatic ring connected to Ru(II). Ru(II)-Pheox
complexes having electron withdrawing groups such as NO2 and
CF3 showed reduced reactivity (Table 2, entries 3 and 4). In
contrast, reactions with chiral Ru(II)-Pheox complexes having
electron donating groups such as OMe showed improved
enantioselectivities, which increased up to 87% ee in moderate
yield (Table 2, entries 5 and 6). Various solvents were also
examined, but the reactivity and enantioselectivity did not
improve significantly (Table 2, entries 7‒10).
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Page 4 of 14
catalytic asymmetric regio- and enantioselective functionalization
report of the highly regio- and enantioselective functionalization
1
2
3
4
of primary C‒H bond did not depend on the steric hindrance of N-
substituents of diazoacetamide. In addition, the highly
enantioselective functionalization of unactivated primary C‒H
bond, such as tert-butyl groups, was achieved by using a suitable
substrate and catalyst.
of the unactivated primary C‒H bonds of the tert-butyl goup.
EXPERIMENTAL SECTION
5
6
7
8
9
General Information of Analysis and Reagents: All reactions
were performed under an atmosphere of argon unless otherwise
noted. Dichloromethane (CH2Cl2) was purchased from Kanto
Chemical Co., Inc.. All reactions were monitored by thin layer
chromatography (TLC), glass plates pre-coated with silica gel
Merck KGaA 60 F254, layer thickness 0.2 mm. The products were
visualized by irradiation with UV light or by treatment with a
solution of phosphomolybdic acid or by treatment with a solution
of p-anisaldehyde. Column chromatography was performed using
silica gel (Merck, Art. No. 7734) or aluminium oxide 90
Table 3. Asymmetric intramolecular C‒H insertion reaction of α-
diazoacetamides using S-Ru(II)-Pheox.
O
O
cat. 4
(5 mol%)
N2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

nN
nN
R'
R'
RT, CH2Cl2
R
R
23a-23g
24a-24g
entr
y
time yield
[h]
ee
diazoacetamide
R
H
[%]a [%]b
1
standardized (Merck, Art. No. 101097). H NMR (500 MHz, 400
MHz) and 13C NMR (125 MHz, 100 MHz) spectra were recorded
on JEOL JNM-ECX500, JEOL JNM-ECS400 spectrometer.
Chemical shifts are reported as δ values (ppm) relative to CDCl3
(7.26 ppm). Optical rotations were performed with a JASCO P-
1030 polarimeter at the sodium D line (1.0 ml sample cell).
Enantiomeric excesses were determined by high-performance
O
N2
1c
7
trace
-
N
(23a)
H
(23b)
2
3
3
3
67
51
87
88
R
O
liquid chromatography (HPLC) analyses with
a JASCO
N2
GULLIVER using Daicel CHIRALPAK or CHIRALCEL
columns. DART mass (positive mode) analyses were performed
on a LC-TOF JMS-T100LP.
N
MeO
(23c)
R
R
O
N2
H
(23d)
N
4d
24
24
0
-
-
Preparation of Diazoacetamides
SO2Ph
tert-Butyl amine (5 mmol, 1 equiv.) and aldehyde (5 mmol, 1
equiv.) were dissolved in MeOH (15 mL) and the resulting
mixture was stirred for 3h at RT, then NaBH4 (6 mmol, 1.2
equiv.) was added portion wise. After 1h, the solution was added
water (15 mL) and extracted with CH2Cl2. The combined organic
layer was dried over Na2So4 and then evaporated under reduced
pressure to give secondary amine. The product was used in the
next step without further purification.
O
N2
H
(23e)
N
5e
NR
Ac
O
H
(23f)
6
3
3
69
81
90
90
N2
N
Bromoacetyl bromide (3.3 mmol, 1.1 equiv.) was slowly added at
0 °C to a stirred solution of amine (3 mmol, 1 equiv.) and Et3N
(3.6 mmol, 1.2 equiv.) in CH2Cl2 (8 mL). The mixture was stirred
at 0 °C and then at RT for 3h. The reaction mixture was washed
with HCl (5%, 7 mL) and the aqueous layer was extracted with
CH2Cl2. The combined organic layer was washed with NaHCO3
aq., followed by brine, and then dried over Na2SO4. The solvent
was removed under reduced pressure to give bromoacetyl product
as brown oil.
R
MeO
(23g)
7f
O
N2
-
8f
7
70
91
N
(23h)
a
b
c
Isolated yield. Determined by chiral HPLC. Major product
was β-lactam 25a (85% yield, dr = 84:16, major 7% ee, minor
45% ee). d Insertion reaction into secondary C‒H bond to provide
To a solution of bromoacetyl product (3.3 mmol, 1equiv.) and N,
N’-ditosylhydrazine (4.5 mmol, 1.5 equiv.) were dissolved in
THF (8 mL) and cooled down to 0 °C, then DBU (6 mmol, 2
equiv.) was added slowly and stirred at 0 °C for 2h. After
quenched with NaHCO3 aq. and extracted with Et2O three times,
the organic layer was dried over Na2SO4 and evaporated to give
crude product. Purification was performed with column
e
γ-lactam 25d proceeded mainly (95% yield, racemic). Strried at
40 °C for 24 h. No reaction. f 7 mol% of catalyst was used.
CONCLUSION
chromatography (Hex/EA
diazoacetamide as yellow oil.
=
20/1~8/1) to give desired
In conclusion, we have achieved the highly regio- and
enantioselective functionalization of unactivated primary C‒H
bonds such as the N-tert-butyl group of various diazoacetamides
by using the Ru(II)-Pheox catalyst. The intramolecular catalytic
asymmetric amide carbene insertion reactions of diazoamide
proceeded rapidly in the presence of Ru(II)-Pheox to give the
corresponding γ-lactam derivatives in moderate to high yields
with high enantioselectivities (up to 91% ee). This is the first
N-benzyl-N-(tert-butyl)-2-diazoacetamide (7a)5q, 6, 9
O
N2
N
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Yellow oil, 51% yield (115.2 mg, 0.49 mmol). 1H NMR (400
(100 MHz, CDCl3) δ 166.3, 138.3, 128.8, 128.3, 126.7, 57.8, 48.6,
1
2
3
4
5
6
7
8
MHz, CDCl3) δ 7.35 (t, J = 7.64 Hz, 2H), 7.26 (t, J = 8.79 Hz,
1H), 7.22 (d, J = 7.64 Hz, 2H), 4.75 (s, 1H), 4.44 (s, 2H), 1.47 (s,
9H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 167.9, 138.8,
128.8, 127.1, 125.5, 58.2, 48.8, 28.8 ppm.
46.9, 37.9, 29.3 ppm. IR (neat) ν 3081, 3023, 2999, 2977, 2925,
2099, 1592, 1408, 1393 cm-1. HRMS (DART) calcd for
C14H20O1N3 [M+H]+: 246.1606, found: 246.1605.
N-(tert-butyl)-2-diazo-N-(4-methoxyphenethyl)acetamide (7g)
N-(tert-butyl)-N-(4-chlorobenzyl)-2-diazoacetamide (7b)6
MeO
O
O
N2
N2
N
N
9
Cl
Yellow oil, 33% yield (106.7 mg, 0.39 mmol). 1H NMR (400
MHz, CDCl3) δ 7.08 (d, J = 8.41 Hz, 2H), 6.86 (d, J = 8.41 Hz,
2H), 4.95 (s, 1H), 3.79 (s, 3H), 3.26 (t, J = 8.79 Hz, 2H), 2.77 (t, J
= 8.41 Hz, 2H), 1.51 (s, 9H) ppm. 13C{1H} NMR (125 MHz,
CDCl3) δ 166.3, 158.4, 130.3, 129.3, 114.2, 57.8, 55.2, 48.5, 47.1,
37.0, 29.3 ppm. IR (neat) ν 2962, 2932, 2104, 1613, 1512, 1404,
1359, 1175 cm-1. HRMS (DART) calcd for C15H22O2N3 [M+H]+:
276.1712, found: 276.1711.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yellow oil, 23% yield (179.7 mg, 0.67 mmol). 1H NMR (400
MHz, CDCl3) δ 7.30 (d, J = 8.41 Hz, 2H), 7.16 (d, J = 8.41 Hz,
2H), 4.71 (s, 1H), 4.40 (s, 2H), 1.46 (s, 9H) ppm. 13C{1H} NMR
(100 MHz, CDCl3) δ167.8, 137.4, 132.8, 129.0, 127.0, 58.2, 48.7,
48.2, 28.9 ppm.
N-(tert-butyl)-2-diazo-N-(4-nitrobenzyl)acetamide (7c)6
O
N2
N-(tert-butyl)-2-diazo-N-(3-phenylpropyl)acetamide (7h)
N
O
NO2
N2
N
1
Yellow solid, 24% yield (97.7 mg, 0.35 mmol). H NMR (400
MHz, CDCl3) δ 8.24 (d, J = 8.41 Hz, 2H), 7.42 (d, J = 8.79 Hz,
2H), 4.66 (s, 1H), 4.54 (s, 2H), 1.46 (s, 9H) ppm. 13C{1H} NMR
(100 MHz, CDCl3) δ 167.7, 147.2, 146.7, 126.5, 124.2, 58.4, 48.9,
48.6, 29.0 ppm. IR (neat) ν 3100, 2924, 2104, 1614, 1518, 1397,
1343 cm-1. HRMS (DART) calcd for C13H17O3N4 [M+H]+:
277.1300, found: 277.1300.
1
Yellow solid, 15% yield (42.8 mg, 0.17 mmol). H NMR (400
MHz, CDCl3) δ 7.31 (t, J = 7.64 Hz, 2H), 7.22 (t, J = 7.64 Hz,
1H), 7.18 (d, J = 6.88 Hz, 2H), 4.58 (s, 1H), 3.01 (t, J = 8.79 Hz,
2H), 2.60 (t, J = 7.26 Hz, 2H), 1.87 (quin, J = 7.26 Hz, 2H), 1.42
(s, 9H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 166.1, 140.6,
128.5, 128.3, 128.2, 126.3, 57.6, 48.0, 44.3, 33.0, 32.8, 29.2 ppm.
IR (neat) ν 3085, 2969, 2935, 2102, 1609, 1478, 1409 cm-1.
HRMS (DART) calcd for C15H22O1N3 [M+H]+: 260.1763, found:
260.1763.
N-(tert-butyl)-2-diazo-N-(4-methylbenzyl)acetamide (7d)6
O
N2
N
N-(tert-butyl)-2-diazo-N-(3-(4-methoxyphenyl)propyl)
acetamide (7i)
Yellow oil, 16% yield (82.9 mg, 0.33 mmol). 1H NMR (400 MHz,
CDCl3) δ 7.13-7.30 (m, 4H), 4.63 (s, 1H), 4.32 (s, 2H), 2.26 (s,
3H), 1.48 (s, 9H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ168.0,
136.2, 133.9, 130.2, 126.9, 126.3, 125.3, 58.0, 48.5, 46.9, 28.6,
18.8 ppm.
O
N2
N
MeO
1
Yellow solid, 22% yield (92.0 mg, 0.31 mmol). H NMR (400
N-(tert-butyl)-2-diazo-N-(4-methoxybenzyl)acetamide (7e)6
MHz, CDCl3) δ 7.09 (d, J = 8.79 Hz, 2H), 6.85 (d, J = 8.79 Hz,
2H), 4.61 (s, 1H), 3.79 (s, 3H), 3.01 (t, J = 8.41 Hz, 2H), 2.53 (t, J
= 7.26 Hz, 2H), 1.83 (quin, J = 9.17 Hz, 2H), 1.42 (s, 9H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 158.0, 132.5, 129.2,
57.6, 55.2, 48.1, 44.3, 33.0, 32.1, 29.2 ppm. IR (neat) ν 2968,
2937, 2100, 1612, 1512, 1405, 1176 cm-1. HRMS (DART) calcd
for C16H24O2N3 [M+H]+: 290.1868, found: 290.1865.
O
N2
N
MeO
Yellow oil, 15% yield (82.5 mg, 0.31 mmol). 1H NMR (400 MHz,
CDCl3) δ 7.13 (d, J = 8.79 Hz, 2H), 6.89 (d, J = 8.41 Hz, 2H),
4.77 (s, 1H), 4.37 (s, 2H), 3.08 (s, 3H,), 1.46 (s, 9H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ167.8, 158.6, 130.7, 126.6,
114.2, 58.2, 55.3, 48.7, 48.2, 28.9 ppm.
2-diazo-N-isopropyl-N-phenethylacetamide (11)
O
N2
N
N-(tert-butyl)-2-diazo-N-phenethylacetamide (7f)2b, 6
Yellow oil, 24% yield (97.7 mg, 0.35 mmol). 1H NMR (400 MHz,
CDCl3) δ 7.19-7.33 (m, 4H), 4.96 (brs, 1H), 3.31 (brs, 2H), 2.87
(t, J = 8.41 Hz, 2H), 1.18 (d, J = 6.88 Hz, 6H) ppm. 13C{1H}
NMR (100 MHz, CDCl3) δ 165.3, 128.6, 126.5, 46.9, 44.1, 36.8,
20.9 ppm. IR (neat) ν 2974, 2102, 1598, 1425, 1357 cm-1. HRMS
(DART) calcd for C13H18O1N3 [M+H]+: 232.1449, found:
232.1449.
O
N2
N
Yellow oil, 32% yield (115.3 mg, 0.47 mmol). 1H NMR (400
MHz, CDCl3) δ 7.32 (t, J = 7.64 Hz, 2H), 7.25 (t, J = 5.35 Hz,
1H), 7.15 (d, J = 6.88 Hz, 2H), 4.97 (s, 1H), 3.30 (t, J = 6.12 Hz,
2H), 2.84 (t, J = 8.41 Hz, 2H), 1.52 (s, 9H) ppm. 13C{1H} NMR
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2-diazo-N-(tert-pentyl)-N-phenethylacetamide (14)
13C{1H} NMR (125 MHz, CDCl3) δ174. 7, 138.9, 128.3, 127.5,
1
126.9, 60.9, 42.7, 34.5, 29.6, 26.8 ppm.
O
2
3
4
N2
N
1-(tert-butyl)-4-phenylazetidin-2-one (9a)2b
O
Yellow oil, 49% yield (126.7 mg, 0.49 mmol). 1H NMR (500
MHz, CDCl3) δ7.32 (t, J = 7.64 Hz, 2H), 7.24 (t, J = 6.50 Hz,
1H), 7.17 (d, J = 7.26 Hz, 2H), 3.28 (t, J = 8.79 Hz, 2H), 2.84 (t, J
= 8.79 Hz, 2H), 2.01 (q, J = 7.64 Hz, 2H), 1.46 (s, 6H), 0.81 (t, J
= 7.64 Hz, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 166.0,
138.2, 128.8, 128.3, 126.7, 61.1, 48.4, 47.2, 38.0, 32.5, 27.3, 8.9
ppm. IR (neat) ν 2968, 2920, 2100, 1610, 1407, 1355, 1168 cm-1.
HRMS (DART) calcd for C15H21ON3 [M+H]+: 260.1757, found:
260.1751.
5
6
7
8
N
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7a
(47.0 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.26 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 1-(tert-butyl)-4-phenylazetidin-2-one 9a as
a colorless oil (43% yield, 17.7 mg, 0.09 mmol). 1H NMR (500
MHz, CDCl3) δ 7.32-7.39 (m, 4H), 7.32-7.27 (m, 1H), 4.55 (dd, J
= 5.35, 2.29 Hz, 1H), 3.22 (dd, J = 14.52, 5.35 Hz, 1H), 2.66 (dd,
J = 14.91, 2.29 Hz, 1H), 1.23 (s, 9H) ppm. 13C{1H} NMR (125
MHz, CDCl3) δ 167.4, 141.0, 128.7, 128.1, 126.3, 54.6, 53.0,
45.9, 28.3, 28.1 ppm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(tert-butyl)-2-diazo-N-ethylacetamide (16)
O
N2
N
Yellow oil, 37% yield (80.5 mg, 0.47 mmol). 1H NMR (400 MHz,
CDCl3) δ 4.95 (s, 1H), 3.17 (q, J = 7.32 Hz, 2H), 1.47 (s, 9H),
1.16 (t, J = 7.02 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3)
δ 166.1, 57.6, 48.3, 39.5, 29.2, 16.7 ppm. IR (neat) ν 2973, 2100,
1606, 1408 cm-1. HRMS (DART) calcd for C8H16O1N3 [M+H]+:
170.1293, found: 170.1293.
1-(4-chlorobenzyl)-5,5-dimethylpyrrolidin-2-one (8b)
O
N
Cl
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7b
(53.15 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
2-diazo-N,N-diisopropylacetamide (18)7
O
N2
N
Hexane/EtOAc
to
give
1-(4-chlorobenzyl)-5,5-
dimethylpyrrolidin-2-one 8b as a colorless oil (59% yield, 28.2
mg, 0.12 mmol). H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.85
Hz, 2H), 7.22 (d, J = 8.54 Hz, 2H), 4.37 (s, 2H), 2.47 (t, J = 7.93
Hz, 2H), 1.87 (t, J = 7.93 Hz, 2H), 1.12 (s, 6H) ppm. 13C{1H}
NMR (100 MHz, CDCl3) δ 174.8, 137.5, 132.7, 129.0, 128.5,
60.9, 42.0, 34.4, 29.5, 26.8 ppm.
1
Yellow oil, 31% yield (132.2 mg, 0.78 mmol). 1H NMR (400
MHz, CDCl3) δ 4.95 (s, 1H). 3.65 (brs, 2H), 1.30 (s, 12H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ 164.5, 47.6, 46.9, 21.1 ppm.
General Procedure for Intramolecular Carbene C−H
Insertion Reaction of α-Diazoacetamides.
1-(tert-butyl)-4-(4-chlorophenyl)azetidin-2-one (9b)
O
To a solution of Ru(II)-Pheox (1 mol%) in CH2Cl2 (2 mL) was
added a solution of diazo compound (0.2 mmol, 1 equiv.) in
CH2Cl2 (2 mL) under argon atmosphere at room temperature. The
reaction mixture was stirred at room temperature for 1 min. The
solvent was removed and residue was purified by silica gel
column chromatography (Hex/EtOAc = 10/1 – 1/1) to give
desired product(s).
N
Cl
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7b
(53.15 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 1-(tert-butyl)-4-(4-chlorophenyl)azetidin-
1-benzyl-5,5-dimethylpyrrolidin-2-one (8a)6
O
1
2-one 9b as a colorless oil (32% yield, 15.1 mg, 0.06 mmol). H
N
NMR (400 MHz, CDCl3) δ 7.30-7.36 (m, 4H), 4.54 (dd, J = 5.49,
2.14 Hz, 1H), 3.24 (dd, J = 14.65, 5.49 Hz, 1H), 2.62 (dd, J =
14.65, 2.44 Hz, 1H), 1.24 (s, 9H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 167.1, 139.7, 133.8, 129.0, 127.6, 54.7, 52.4, 46.0, 28.1
ppm. IR (neat) ν 2973, 1747, 1490, 1367, 1089 cm-1. HRMS
(DART) calcd for C13H17O1N1Cl1 [M+H]+: 238.0998, found:
238.0995.
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7a
(47.0 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.26 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 1-benzyl-5,5-dimethylpyrrolidin-2-one 8a
1
5,5-dimethyl-1-(4-nitrobenzyl)pyrrolidin-2-one (8c)
as a colorless oil (51 % yield, 21.0 mg, 0.103 mmol). H NMR
O
(500 MHz, CDCl3) δ 7.30-7.19 (m, 5H), 4.41 (s, 2H), 2.48 (t, J =
8.03 Hz, 2H), 1.87 (t, J = 8.03 Hz, 2H), 1.12 (s, 6H) ppm.
N
NO2
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This compound was prepared according to the typical procedure
dihydrocyclohepta[c]pyrrol-1(2H)-one 10e as a brown oil (94%
yield, 44 mg, 0.19 mmol). H NMR (500 MHz, CDCl3) δ 6.04-
1
1
2
3
4
for intramolecular C‒H insertion reaction of α-diazoacetamide 7c
(55.26 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 5,5-dimethyl-1-(4-nitrobenzyl)pyrrolidin-
5.99 (m, 2H), 5.68 (d, J = 6.88 Hz, 1H), 5.46 (dd, J = 10.32, 4.20
Hz, 1H), 4.24 (dd, J = 24.46, 14.91 Hz, 2H), 3.62 (s, 3H), 3.13
(bs, 1H), 1.45 (s, 9H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ
174.0, 159.1, 124.6, 124.0, 123.9, 117.0, 102.6, 54.6, 54.1, 49.6,
47.3, 27.5 ppm.
5
1
2-one 8c as a colorless oil (83% yield, 41.2 mg, 0.16 mmol). H
6
7
8
9
NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.32 Hz, 2H), 7.45 (d, J =
7.63 Hz, 2H), 4.47 (s, 2H), 2.51 (t, J = 7.63 Hz, 2H), 1.93 (t, J =
7.63 Hz, 2H), 1.14 (s, 6H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 175.0, 147.1, 146.5, 128.3, 123.7, 61.0, 42.3, 34.4, 29.4,
26.9 ppm. IR (neat) ν 2972, 1673, 1518, 1340 cm-1. HRMS
(DART) calcd for C13H17O3N2 [M+H]+: 249.1239, found:
249.1232.
5,5-dimethyl-1-phenethylpyrrolidin-2-one (8f)6
O
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7f
(49.06 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 5,5-dimethyl-1-phenethylpyrrolidin-2-one
5,5-dimethyl-1-(4-methylbenzyl)pyrrolidin-2-one (8d)6
O
N
Me
1
8f as a colorless oil (94% yield, 40.5 mg, 0.19 mmol). H NMR
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7d
(49.06 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
(400 MHz, CDCl3) δ 7.29 (t, J = 7.32 Hz, 2H), 7.23 (d, J = 7.63
Hz, 2H), 7.20 (t, J = 7.32 Hz, 1H), 3.29 (dd, J = 10.38, 7.63 Hz,
2H), 2.89 (dd, J = 8.24, 5.49 Hz, 2H), 2.38 (t, J = 7.93 Hz, 2H),
1.84 (t, J = 7.93 Hz, 2H), 1.16 (s, 6H) ppm. 13C{1H} NMR (100
MHz, CDCl3) δ 174.5, 139.3, 128.8, 128.3, 126.2, 60.5, 41.5,
35.4, 34.1, 29.5, 26.7 ppm. IR (neat) ν 3026, 2965, 2933, 2873,
1691, 1404, 1369 cm-1. HRMS (DART) calcd for C14H19O1N1Na1
[M+Na]+: 240.1364, found: 240.1363.
Hexane/EtOAc
to
give
5,5-dimethyl-1-(4-
methylbenzyl)pyrrolidin-2-one 8d as a colorless oil (47% yield,
1
20.0 mg, 0.09 mmol). H NMR (500 MHz, CDCl3) δ 7.09-7.16
(m, 4H), 4.40 (s, 2H), 2.51 (t, J = 7.63 Hz, 2H), 2.32 (s, 3H), 1.92
(t, J = 7.93 Hz, 2H), 1.12 (s, 6H) ppm. 13C{1H} NMR (125 MHz,
CDCl3) δ 174.7, 135.9, 135.1, 130.1, 127.1, 126.8, 125.9, 60.9,
40.4, 34.5, 29.7, 26.6, 19.2 ppm.
1-(4-methoxyphenethyl)-5,5-dimethylpyrrolidin-2-one (8g)
MeO
O
N
1-(tert-butyl)-4-(p-tolyl)azetidin-2-one (9d)
O
N
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7g
(55.07 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Me
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7d
(49.06 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 1-(tert-butyl)-4-(p-tolyl)azetidin-2-one 9d
as a colorless oil (47% yield, 20.0 mg, 0.09 mmol). 1H NMR (500
MHz, CDCl3) δ 7.47 (d, J = 7.64 Hz, 1H), 7.26-7.20 (m, 1H), 7.16
(t, J = 7.26 Hz, 1H), 7.12 (d, J = 7.64 Hz, 1H), 4.87-4.80 (m, 1H),
3.21 (dd, J = 14.52, 5.35 Hz, 1H), 2.55 (d, J = 14.52 Hz, 1H), 1.26
(s, 9H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 167.8, 138.9,
134.6, 130.5, 127.5, 126.5, 125.0, 54.3, 48.7, 45.3, 27.9, 19.0
ppm.
Hexane/EtOAc
to
give
1-(4-methoxyphenethyl)-5,5-
dimethylpyrrolidin-2-one 8g as a colorless oil (75% yield, 37.1
mg, 0.15 mmol). H NMR (500 MHz, CDCl3) δ 7.15 (d, J = 8.24
1
Hz, 2H), 6.83 (d, J = 8.54 Hz, 2H), 3.78 (s, 3H), 3.26 (dd, J =
7.93, 5.80 Hz, 2H), 2.83 (dd, J = 8.24, 5.49 Hz, 2H), 2.38 (t, J =
7.93 Hz, 2H), 1.84 (t, J = 7.93 Hz, 2H), 1.16 (s, 6H) ppm.
13C{1H} NMR (125 MHz, CDCl3) δ 174.5, 158.1, 131.4, 129.7,
113.8, 60.6, 55.2, 41.8, 34.6, 34.1, 29.6, 26.8 ppm. IR (neat) ν
2965, 2934, 2835, 1680, 1512, 1405 cm-1. HRMS (DART) calcd
for C15H25O2N2 [M+NH4]+: 265.1916, found: 265.1916.
1-(tert-butyl)-4-(4-methoxybenzyl)azetidin-2-one (9g)
2-(tert-butyl)-6-methoxy-3,8a-dihydrocyclohepta[c]pyrrol-
1(2H)-one (10e)6
MeO
O
N
MeO
N
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7g
(55.07 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
O
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7e
(52.3 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc
to
give
1-(tert-butyl)-4-(4-
methoxybenzyl)azetidin-2-one 9g as a colorless oil (18% yield,
8.9 mg, 0.035 mmol). H NMR (500 MHz, CDCl3) δ 7.15 (d, J =
Hexane/EtOAc
to
give
2-(tert-butyl)-6-methoxy-3,8a-
1
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8.85 Hz, 2H), 6.86 (d, J = 8.54 Hz, 2H), 3.79 (s, 3H), 3.32-3.44
CDCl3) δ 7.34 (t, J = 7.26 Hz, 2H), 7.26 (t, J = 2.68 Hz, 1H), 7.23
1
2
3
4
5
6
7
8
(m, 2H), 2.73 (dd, J = 16.48, 8.85 Hz, 1H), 2.50 (dd, J = 16.78,
9.16 Hz, 1H), 1.42 (s, 9H) ppm. 13C{1H} NMR (125 MHz,
CDCl3) δ 174.2, 158.5, 134.6, 129.7, 127.6, 114.1, 55.2, 54.0,
53.3, 40.8, 36.3, 27.7 ppm. IR (neat) ν 2971, 2935, 2910, 1682,
1514, 1249, 1034 cm-1. HRMS (DART) calcd for C15H25O2N2
[M+NH4]+: 265.1916, found: 265.1913.
(d, J = 8.41 Hz, 2H), 4.45 (sep, J = 6.88 Hz, 1H), 3.72 (dd, J =
9.56, 8.41 Hz, 1H), 3.52 (quin, J = 8.41 Hz, 1H), 3.31 (dd, J =
9.56, 6.88 Hz, 1H), 2.82 (dd, J = 16.82, 9.17 Hz, 1H), 2.56 (dd, J
= 16.82, 8.41 Hz, 1H), 1.17 (d, J = 6.50 Hz, 3H), 1.14 (d, J = 6.88
Hz, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 172.9, 142.6,
128.8, 126.9, 126.6, 49.1, 42.3, 39.4, 37.2, 19.8, 19.6 ppm. IR
(neat) ν 3470, 2971, 2933, 2874, 1740, 1691, 1680, 1426, 1366
cm-1. HRMS (DART) calcd for C13H18O1N1 [M+H]+: 204.1388,
found: 204.1385.
5,5-dimethyl-1-(3-phenylpropyl)pyrrolidin-2-one (8h)
O
9
N
4,5,5-trimethyl-1-phenethylpyrrolidin-2-one (15)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7h
(42.8 mg, 0.165 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 14
(25.94 mg, 0.1 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(0.6 mg, 0.001 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 4,5,5-trimethyl-1-phenethylpyrrolidin-2-
Hexane/EtOAc
to
give
5,5-dimethyl-1-(3-
phenylpropyl)pyrrolidin-2-one 8h as a colorless oil (99 % yield,
37.9 mg, 0. 165 mmol). 1H NMR (500 MHz, CDCl3) δ 7.27 (t, J =
7.63 Hz, 2H), 7.22-7.15 (m, 3H), 3.15 (dd, J = 7.93 Hz, 2H), 2.65
(t, J = 7.63 Hz, 2H), 2.37 (t, J = 7.93 Hz, 2H), 1.98-1.86 (m, 2H),
1.83 (t, J = 8.24 Hz, 2H), 1.19 (s, 6H) ppm. 13C{1H} NMR (125
MHz, CDCl3) δ 174.4, 141.5, 128.3, 128.2, 125.8, 60.6, 39.2,
34.2, 33.5, 31.2, 29.6, 26.9 ppm. IR (neat) ν 2965, 2932, 1681,
1405, 1370 cm-1. HRMS (DART) calcd for C15H25O1N2
[M+NH4]+: 249.1966, found: 249.1967.
1
one 15 as a colorless oil (81% yield, 18.7 mg, 0.08 mmol). H
NMR (500 MHz, CDCl3) δ 7.30-7.18 (m, 5H), 3.47 (ddd, J =
13.76, 10.32, 5.35 Hz, 1H), 3.11 (ddd, J = 13.76, 10.32, 6.12),
2.93 (ddd, J = 13.00, 10.32, 5.35 Hz, 1H), 2.85 (ddd, J = 13.00,
10.32, 6.12 Hz, 1H), 2.50-2.40 (m, 1H), 2.09-1.98 (m, 2H), 1.11
(s, 3H), 0.99 (d, J = 6.50 Hz, 3H), 0.95 (s, 3H) ppm. 13C{1H}
NMR (125 MHz, CDCl3) δ 174.2, 139.4, 128.8, 128.4, 126.2,
63.1, 41.8, 38.8, 37.7, 35.6, 26.0, 20.1, 14.0 ppm. IR (neat) ν
2965, 1678, 1407, 1172 cm-1. HRMS (DART) calcd for
C14H20ON3 [M+H]+: 232.1696, found: 232.1692.
1-(3-(4-methoxyphenyl)propyl)-5,5-dimethylpyrrolidin-2-one
(8i)
O
N
MeO
1-ethyl-5,5-dimethylpyrrolidin-2-one (17)
O
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 7i
(57.60 mg, 0.199 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 1-(3-(4-methoxyphenyl)propyl)-5,5-
dimethylpyrrolidin -2-one 8i as a green oil (96% yield, 50.1 mg,
N
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 16
(33.8 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 1-ethyl-5,5-dimethylpyrrolidin-2-one 17 as
1
0.19 mmol). H NMR (500 MHz, CDCl3) δ 7.11 (d, J = 8.54 Hz,
2H), 6.82 (d, J = 8.54 Hz, 2H), 3.78 (s, 3H), 3.13 (t, J = 7.93 Hz,
2H), 2.59 (t, J = 7.63 Hz, 2H), 2.37 (t, J = 7.63 Hz, 2H), 1.88-1.90
(m, 2H), 1.83 (t, J = 7.93 Hz, 2H), 1.19 (s, 6H) ppm. 13C{1H}
NMR (125 MHz, CDCl3) δ 174.4, 157.7, 133.6, 129.1, 113.7,
60.6, 55.2, 39.2, 34.2, 32.6, 31.4, 29.6, 26.9 ppm. IR (neat) ν
2965, 2935, 1681, 1406, 1177 cm-1. HRMS (DART) calcd for
C16H24O2N1 [M+H]+: 262.1807, found: 262.1807.
1
a colorless oil (90% yield, 25.3 mg, 0.18 mmol). H NMR (500
MHz, CDCl3) δ 3.20 (q, J = 7.32 Hz, 2H), 2.37 (t, J = 7.93 Hz,
2H), 1.84 (t, J = 8.24 Hz, 2H), 1.23 (s, 6H), 1.16 (t, J = 7.02 Hz,
3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 174.1, 60.6, 34.3,
33.9, 29.7, 27.0, 15.0 ppm. IR (neat) ν 2969, 2936, 1682, 1409
cm-1. HRMS (DART) calcd for C8H16O1N1 [M+H]+: 142.1232,
found: 142.1233.
1-isopropyl-4-phenylpyrrolidin-2-one (12)
O
1-isopropyl-5-methylpyrrolidin-2-one (19)
N
O
N
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 11
(46.26 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 1-isopropyl-4-phenylpyrrolidin-2-one 12
as a colorless oil in 60% yield (the yield was determined by crude
1H NMR, the isolated yield was 52% yield). 1H NMR (500 MHz,
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 18
(33.85 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 1-isopropyl-4,4-dimethylazetidin-2-one 19
1
as a colorless oil (28% yield, 7.8 mg, 0.06 mmol). H NMR (500
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MHz, CDCl3) δ 4.15 (sep, J = 6.71 Hz, 1H), 3.75-3.84 (m, 1H),
1.38 (s, 9H) ppm. 13C{1H} NMR (125 MHz, CDCl3) 171.28,
1
2
3
4
2.46 (dt, J = 16.78, 8.85 Hz, 1H), 2.27 (ddd, J = 16.78, 9.77, 4.88
Hz, 1H), 2.08-2.20 (m, 1H), 1.63-1.54 (m, 1H), 1.26 (d, J = 3.36
Hz, 3H), 1.24 (d, J = 1.22 Hz, 3H), 1.23 (d, J = 4.27 Hz, 3H) ppm.
13C{1H} NMR (125 MHz, CDCl3) δ 174.4, 52.6, 43.9, 30.4, 27.3,
22.3, 21.7, 19.5 ppm.
139.98, 128.51, 127.12, 126.11, 58.21, 50.14, 28.68, 10.97 ppm.
IR (neat) ν 2965, 2054, 1622, 1364, 1201 cm-1. HRMS (DART)
calcd for C14H20ON3 [M+H]+: 246.1606, found: 246.1606.
N-(tert-butyl)-2-diazo-N-phenethylpropanamide (23b)5k
5
6
7
8
O
1-isopropyl-4,4-dimethylazetidin-2-one (20)
N
N2
9
O
N
Yellow oil, 75% yield (195.0 mg, 0.75 mmol). 1H NMR (500
MHz, CDCl3) δ 7.30 (t, J = 7.63 Hz, 2H), 7.22 (t, J = 7.02 Hz,
1H), 7.17 (d, J = 7.02 Hz, 2H), 3.44 (t, J = 7.93 Hz, 2H), 2.86 (t, J
= 8.24 Hz, 2H), 1.91 (s, 3H), 1.45 (s, 9H) ppm. 13C{1H} NMR
(125 MHz, CDCl3) δ 171.4, 138.8, 128.6, 128.5, 126.5, 57.3, 52.9,
47.9, 38.0, 29.1, 10.7 ppm. IR (neat) ν 2972, 2920, 2052, 1626,
1454, 1390 cm-1. HRMS (DART) calcd for C15H22O1N3 [M+H]+:
260.1762, found: 260.1760.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This compound was prepared according to the typical procedure
for intramolecular C‒H insertion reaction of α-diazoacetamide 18
(33.85 mg, 0.2 mmol, 1 equiv.) in the presence of Ru(II)-Pheox
(1.27 mg, 0.002 mmol, 1 mol%). The resulting mixture was
purified by silica gel column chromatography with
Hexane/EtOAc to give 1-isopropyl-5-methylpyrrolidin-2-one 20
as a colorless oil (67% yield, 19.0 mg, 0.13 mmol). 1H NMR (500
MHz, CDCl3) δ 3.51 (sep, J = 7.02 Hz, 1H), 2.58 (s, 2H), 1.34 (s,
6H), 1.24 (d, J = 8.24 Hz) ppm. 13C{1H} NMR (125 MHz,
CDCl3) δ 165.6, 55.9, 50.2, 44.3, 26.1, 21.7 ppm.
N-(tert-Butyl)-2-diazo-N-(4-methoxyphenethyl)propanamide
(23c)
MeO
O
N
Preparation of α-methyl diazoacrtamide
N2
Yellow oil, 54% yield (61.0 mg, 0.21 mmol). 1H NMR (500 MHz,
CDCl3) δ 7.09 (d, J = 8.79 Hz, 2H), 6.85 (d, J = 8.79 Hz, 2H),
2.87 (s, 3H), 3.39 (t, J = 8.03 Hz, 2H), 2.79 (t, J = 8.03 Hz, 2H),
1.92 (s, 3H), 1.44 (s, 9H) ppm. 13C{1H} NMR (125 MHz, CDCl3)
δ 171.3, 158.2, 130.8, 129.5, 114.0, 57.3, 55.2, 52.7, 48.1, 37.1,
29.1, 10.8 ppm. IR (neat) ν 2964, 2932, 2053, 1624, 1512, 1247
cm-1. HRMS (DART) calcd for C16H27O2N4 [M+NH4]+:
307.2134, found: 307.2136.
A solution of Pyruvic Acid (5 mmol, 1 equiv.) in CH2Cl2 (6 mL)
was added catalytic amount of DMF (2 drops) and Oxalyl
Chloride (6 mmol, 1.2 equiv.). The reaction mixture was stirred at
RT for 2 h. The mixture was cooled down to 0 °C and a solution
of amine (7.5 mmol, 1.5 equiv.) and DIPEA (12 mmol, 2.4 equiv)
was slowly added with CH2Cl2 (1 mL). The reaction mixture was
stirred at RT overnight. The reaction was quenched by water and
extracted with CH2Cl2. The combined organic layer was washed
with brine and dried over Na2SO4. The solvent was removed by
evaporator.
Purification
was
performed
by
column
N-(tert-butyl)-2-diazo-N-phenethyl-2-(phenylsulfonyl)
acetamide (23d)5d, 5q
chromatography to give the intermediate as a colorless oil.
Intermediate (4.58 mmol, 1 equiv.) was suspended in MeOH (10
mL). The suspension was heated to 65 °C, a solution was added
Tosylhydrazine (5.04 mmol, 1.1 equiv.) in MeOH (10 mL). The
reaction mixture was stirred at 65 °C for 24 h, and then allowed to
reach room temperature. The mixture was extracted with CH2Cl2
and H2O. The corresponding tosylhydrazone was collected as a
white crystal by filtration with Et2O and was used for next step
without further purification.
N2
N
SO2Ph
O
To a solution of a secondary amine (1 mmol) and TEA (0.17 mL,
1.2 mmol) in dry CH2Cl2 (2 mL), was slowly added α-
bromoacetyl bromide (0.096 mL, 1.1 mmol) at 0 ˚C. The mixture
was stirred at 0 ˚C and then RT for 1 h. The reaction mixture was
washed with 1N HCl, and the aqueous layer was extracted with
CH2Cl2. The combined organic layer were washed with saturated
NaHCO3 solution, followed by brine, dried over Na2SO4, filtered,
and concentrated to give an α -bromoacetyl amide, which was
used for next step without further purification.
A solution of tosylhydrazone (1.12 mmol, 1 equiv.) in THF (9
mL) was treated with a solution of NaOH (5.62 mmol, 5 equiv.) in
H2O (9 mL). The reaction mixture was stirred at 50 °C for 24 h.
The aqueous layer was adjusted to pH = 7 by addition of dry-ice
and extracted with EtOAc. The combined organic layer was dried
over Na2SO4, and the solvent was evaporated in vacuo. The
mixture was purified by column chromatography (Aluminum
Oxide, Hex/EA = 3/1) to give desired diazoacetamide as a yellow
oil.
To a solution of α-bromoacetyl amide (1 mmol) in CH2Cl2 (5
mL), was added benzenesulfonic acid sodium salt (180.6 mg, 1.1
mmol). The reaction mixture was stirred for 1 h at RT and was
poured into EtOAc. The mixture was washed three times with
water, then once with brine, dried over Na2SO4, filtered and
concentrated. The mixture was purified by column
chromatography to give α-phenylsulfonyl-acetamide (combined
yield: 55%).
N-benzyl-N-(tert-butyl)-2-diazopropanamide (23a)
O
N
N2
To a mixture of α-phenylsulfonyl-acetamide (0.5 mmol) and p-
ABSA (132.1 mg, 0.55 mmol) in dry CH3CN (2.5 mL), DBU was
slowly added at 0 ˚C. Then the resulting mixture was stirred for
30 min at RT, and the solvent was removed by evaporation. The
Yellow oil, 18% yield (49.1 mg, 0.2 mmol, determined by 1H
NMR, product was not pure). 1H NMR (500 MHz, CDCl3) δ 7.35-
7.28 (m, 2H), 7.23 (d, J = 7.26 Hz, 2H), 4.50 (s, 2H), 1.82 (s, 3H),
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O
residue was diluted with Et2O and the mixture was washed with
1
2
3
4
5
6
7
8
1N NaOH, water and brine. The yellow organic layer was dried
over Na2SO4, filtered and concentrated. The residue was purified
by column chromatography to give N-(tert-butyl)-2-diazo-N-
phenethyl-2-(phenylsulfonyl)acetamide 23d (0.43 mmol, 163.1
N
N2
MeO
Yellow oil, 39% yield (90.0 mg, 0.29 mmol). 1H NMR (500 MHz,
CDCl3) δ 7.08 (d, J = 8.79 Hz, 2H), 6.83 (d, J = 8.41 Hz, 2H),
3.79 (s, 3H), 3.21 (t, J = 7.64 Hz, 2H), 2.52 (t, J = 7.64 Hz, 2H),
1.90 (s, 3H), 1.86 (quin, J = 7.64 Hz, 2H), 1.37 (s, 9H3) ppm.
13C{1H} NMR (125 MHz, CDCl3) δ 171.5, 158.0, 133.2, 129.2,
113.9, 57.2, 55.3, 52.5, 46.0, 33.8, 32.5, 29.0, 10.9 ppm. IR (neat)
ν 2963, 2932, 2054, 1622, 1512, 1246 cm-1. HRMS (DART) calcd
for C17H29O2N4 [M+NH4]+: 321.2290, found: 321.2291.
1
mg, 86% yield) as a yellow oil. H NMR (500 MHz, CDCl3) δ
7.93 (d, J = 8.0 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.6
Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.16 (d,
J = 7.6 Hz, 2H), 3.70 (t, J = 7.8 Hz, 2H), 2.87 (t, J = 7.8 Hz, 2H),
1.39 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ 159.8, 142.0,
137.8, 133.7, 129.1, 128.7, 127.5, 126.8, 75.3, 58.4, 49.1, 38.2,
28.8 ppm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(tert-butyl)-2-diazo-3-oxo-N-phenethylbutanamide (23e)5d,
N-(tert-butyl)-2-diazo-N-ethylpropanamide (23h)
5q
O
N
N2
N2
N
O
O
Yellow oil, 48% yield (87.4 mg, 0.47 mmol). 1H NMR (500 MHz,
CDCl3) δ 3.31 (q, J = 6.88 Hz, 2H), 1.98 (s, 3H), 1.40 (s, 9H),
1.20 (t, J = 7.26 Hz, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3)
δ171.2, 57.2, 52.3, 40.6, 28.9, 17.6, 11.0 ppm. IR (neat) ν 2975,
2929, 2052, 1626, 1379, 1362 cm-1. HRMS (DART) calcd for
C9H21O1N4 [M+NH4]+: 201.1715, found: 201.1711.
To a solution of diketene (0.46 mL, 6 mmol, 1.7 equiv.) in CH2Cl2
(0.5 mL) was slowly added secondary amine (620 mg, 3.5 mmol,
1 equiv.) in THF (5 mL). The reaction mixture was heated to
reflux for 1 h and stirred at room temperature for 12 h. NH4Cl aq.
(15 mL) was added and the combined mixture was extracted with
CH2Cl2. The organic layer was washed with brine and dried over
MgSO4. The solvent was removed under reduced pressure to give
desired β-ketoamide product (809 mg, 3.1 mmol, 89% yield),
which was used for next step without further purification.
General Procedure for Asymmetric Intramolecular Carbene
C−H Insertion Reaction of α-Diazoacetamides.
To a solution of Ru(II)-Pheox (5 mol%) in CH2Cl2 (2 mL) was
added a solution of diazo compound (0.2 mmol, 1 equiv.) in
CH2Cl2 (2 mL) under argon atmosphere at room temperature. The
reaction mixture was stirred at room temperature. The solvent was
removed and residue was purified by aluminum oxide column
chromatography (Hex/EtOAc = 10/1 – 1/1) to give desired
product.
To a mixture of β-ketoamide product (251 mg, 0.96 mmol, 1
equiv.) and p-ABSA (347 mg, 1.45 mmol, 1.5 equiv.) in CH3CN
(2 mL) was slowly added DBU (0.21 mL, 1.45 mmol, 1.5 equiv.)
at 0 °C. The mixture was stirred for 3 h at room temperature. The
reaction mixture was diluted with H2O (2 mL) followed by
extraction with Et2O. After washing with NaHCO3 aq. and brine,
the combined organic layer was dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (Hex/EA = 5/1) to give N-(tert-
butyl)-2-diazo-3-oxo-N-phenethylbutanamide 23e (181 mg, 0.63
mmol, 66% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3)
δ 7.39 (t, J = 7.26 Hz, 2H), 7.23 (t, J = 7.64 Hz, 1H), 7.15 (d, J =
6.88 Hz, 2H), 3.61 (t, J = 7.26 Hz, 2H), 2.07 (t, J = 7.26 Hz, 2H),
2.15 (s, 3H), 1.55 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ
137.9, 128.7, 128.7, 126.8, 58.0, 49.1, 38.1, 29.0, 26.7 ppm.
3,5,5-trimethyl-1-phenethylpyrrolidin-2-one (24b)
O

N
This compound was prepared according to the typical procedure
for asymmetric intramolecular C‒H insertion reaction of α-
diazoacetamide 23b (44.3 mg, 0.17 mmol, 1 equiv.) in the
presence of p-MeO-Ru(II)-Pheox (5.3 mg, 0.008 mmol, 5 mol%).
The resulting mixture was purified by column chromatography
using aluminium oxide with Hexane/EtOAc = 10/1 to give 3,5,5-
trimethyl-1-phenethylpyrrolidin-2-one 24b as a colorless oil (67%
N-(tert-butyl)-2-diazo-N-(3-phenylpropyl)propanamide (23f)
O
N
N2
1
yield, 26.3 mg, 0.11 mmol). H NMR (500 MHz, CDCl3) δ 7.30-
1
7.26 (m, 2H), 7.25-7.17 (m, 3H), 3.44 (ddd, J = 15.56, 10.38, 5.49
Hz, 1H), 3.14 (ddd, J = 13.43, 10.07, 6.41 Hz, 1H), 2.98-2.80 (m,
2H), 2.52 (sext, J = 7.02 Hz, 1H), 2.12 (dd, J = 12.21, 8.54 Hz,
1H), 1.47-1.38 (m, 1H), 1.22 (d, J = 7.02 Hz, 3H), 1.17 (s, 3H,),
1.12 (s, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ176.9,
139.4, 128.8, 128.3, 126.2, 58.4, 43.4, 41.7, 35.4, 35.0, 28.2, 25.7,
16.4 ppm. IR (neat) ν 2965, 1681, 1407 cm-1. HRMS (DART)
Yellow oil, 21% yield, 2 steps (137.0 mg, 0.5 mmol). H NMR
(500 MHz, CDCl3) δ 7.29 (t, J = 7.32 Hz, 2H), 7.20 (t, J = 7.32
Hz, 1H), 7.17 (d, J = 7.02 Hz, 2H), 3.22 (t, J = 7.32 Hz, 2H), 2.58
(t, J = 7.63 Hz, 2H), 1.89 (s, 3H), 1.89 (quin, J = 7.93 Hz, 2H),
1.37 (s, 9H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 171.4,
141.0, 128.4, 128.2, 126.0, 57.1, 52.4, 45.9, 33.5, 33.3, 28.9, 10.8
ppm. IR (neat) ν 2971, 2054, 1624, 1361, 1297 cm-1. HRMS
(DART) calcd for C16H24ON3 [M+H]+: 274.1919, found:
274.1919.
calcd for C15H22O1N1 [M+H]+: 232.1701, found: 232.1700. [α] D
25
= ‒23.2 (c = 1.305, CHCl3). The ee value was determined by
chiral HPLC analysis, Column (CHIRALPAK IF-3), UV detector
230 nm, eluent: Hex/IPA = 10/1, Flow late = 1.0 mL/min, tR = 12
min (major product), tR = 15 min (minor product).
N-(tert-butyl)-N-(3-(4-methoxyphenyl)propyl)-2-oxopropan
amide (23g)
1-(4-methoxyphenethyl)-3,5,5-trimethylpyrrolidin-2-one (24c)
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The Journal of Organic Chemistry
MeO
presence of p-MeO-Ru(II)-Pheox (9.1 mg, 0.01 mmol, 7 mol%).
O
1
2
3
The resulting mixture was purified by column chromatography
using aluminium oxide with Hexane/EtOAc = 3/2 at 0 °C to give
1-(3-(4-methoxy phenyl)propyl)-3,5,5-trimethylpyrrolidin-2-one

N
1
24f as a colorless oil (81% yield, 44.4 mg, 0.16 mmol). H NMR
4
5
6
7
8
9
This compound was prepared according to the typical procedure
for asymmetric intramolecular C‒H insertion reaction of α-
diazoacetamide 23c (46.0 mg, 0.159 mmol, 1 equiv.) in the
presence of p-MeO-Ru(II)-Pheox (5.3 mg, 0.008 mmol, 5 mol%).
The resulting mixture was purified by column chromatography
using aluminium oxide with Hexane/EtOAc = 9/1 to give 24c as a
colorless oil (51% yield, 21 mg, 0.08 mmol). 1H NMR (500 MHz,
CDCl3) δ 7.15 (d, J = 8.41 Hz, 2H), 6.83 (d, J = 8.41 Hz, 2H),
3.78 (s, 3H), 3.40 (ddd, J = 15.67, 10.32, 5.35 Hz, 1H), 3.11 (ddd,
J = 13.38, 10.32, 5.73 Hz, 1H), 2.86 (ddd, J = 15.67, 9.94, 5.35
Hz, 1H), 2.78 (ddd, J = 13.38, 10.70, 6.50 Hz, 1H), 2.51 (sext, J =
7.26 Hz, 1H), 2.11 (dd, J = 12.23, 8.41 Hz, 1H), 1.43 (dd, J =
12.23, 10.32 Hz, 1H), 1.21 (d, J = 7.26 Hz, 3H), 1.18 (s, 3H), 1.12
(s, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ176.8, 158.0,
131.5, 129.8, 113.7, 58.4, 55.2, 43.4, 41.9, 35.0, 34.5, 28.3, 25.8,
16.4 ppm. IR (neat) ν 2964, 2931, 1686, 1675, 1512, 1459, 1357
(500 MHz, CDCl3) δ 7.11 (d, J = 8.54 Hz, 2H), 6.81 (d, J = 8.24
Hz, 2H), 3.77 (s, 3H), 3.25 (ddd, J = 14.04, 10.38, 5.29 Hz, 1H),
3.01 (ddd, J = 15.56, 10.38, 5.19 Hz, 1H), 2.63-2.55 (m, 2H), 2.49
(sext, J = 7.93 Hz, 1H), 2.09 (dd, J = 12.51, 8.54 Hz, 1H), 1.96-
1.73 (m, 2H), 1.42 (dd, J = 12.21, 10.38 Hz, 1H), 1.23 (s, 3H),
1.19 (d, J = 7.32 Hz, 3H), 1.13 (s, 3H) ppm. 13C{1H} NMR (125
MHz, CDCl3) δ176.7, 157.7, 133.6, 129.1, 113.7, 58.4, 55.2, 43.5,
39.3, 35.0, 32.5, 31.3, 28.4, 25.8, 16.4 ppm. IR (neat) ν 2964,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2931, 1681, 1512, 1408, 1370 cm-1. HRMS (DART) calcd for
25
C17H29O2N2 [M+NH4]+: 293.2229, found: 293.2228. [α]
=
D
‒15.7 (c = 1.540, CHCl3). The ee value was determined by chiral
HPLC analysis, Column (CHIRALPAK IF-3), UV detector 230
nm, eluent: Hex/IPA = 20/1, Flow late = 1.0 mL/min, tR = 28 min
(major product), tR = 35 min (minor product).
cm-1. HRMS (DART) calcd for C16H27O2N2 [M+NH4]+:
1-ethyl-3,5,5-trimethylpyrrolidin-2-one (24g)
25
O
279.2072, found: 279.2072. [α]
= ‒20.1 (c = 1.045, CHCl3).
D
The ee value was determined by chiral HPLC analysis, Column
(CHIRALPAK IF-3), UV detector 230 nm, eluent: Hex/IPA =
20/1, Flow late = 1.0 mL/min, tR = 31 min (major product), tR =
43 min (minor product).
*
N
This compound was prepared according to the typical procedure
for asymmetric intramolecular C‒H insertion reaction of α-
diazoacetamide 23g (20.0 mg, 0.11 mmol, 1 equiv.) in the
presence of p-MeO-Ru(II)-Pheox (5.0 mg, 0.007 mmol, 7 mol%).
The resulting mixture was purified by column chromatography
using aluminium oxide with Hexane/EtOAc = 8/1-6/1 to give 1-
ethyl-3,5,5-trimethylpyrrolidin-2-one 24g as a colorless oil (70 %
3,5,5-trimethyl-1-(3-phenylpropyl)pyrrolidin-2-one (24e)
O

N
1
yield, 11.8 mg, 0.07 mmol). H NMR (500 MHz, CDCl3) δ 3.29
This compound was prepared according to the typical procedure
for asymmetric intramolecular C‒H insertion reaction of α-
diazoacetamide 23e (49.4 mg, 0.18 mmol, 1 equiv.) in the
presence of p-MeO-Ru(II)-Pheox (6.0 mg, 0.009 mmol, 5 mol%).
The resulting mixture was purified by column chromatography
using aluminium oxide with Hexane/EtOAc = 8/1-6/1 to give
(dq, J = 7.26, 14.14 Hz, 1H,), 3.08 (dq, J = 7.26, 14.14 Hz, 1H),
2.53-2.43 (m, 1H), 2.11 (dd, J = 12.61, 8.79 Hz, 1H), 1.44 (dd, J
= 12.23, 10.32 Hz, 1H), 1.28 (s, 3H), 1.19 (d, J = 6.88 Hz, 3H),
1.17 (s, 3H), 1.15 (t, J = 7.26 Hz, 3H) ppm. 13C{1H} NMR (125
MHz, CDCl3) δ 176.4, 58.5, 43.5, 35.1, 34.1, 28.5, 25.9, 16.4,
15.0 ppm. HRMS (DART) calcd for C9H18O1N1 [M+H]+:
3,5,5-trimethyl-1-(3-phenylpropyl)pyrrolidin-2-one 24e as
a
156.1388, found: 156.1380. IR (neat) ν 2967, 1683, 1410 cm-1. [α]
1
colorless oil (69% yield, 30.5 mg, 0.12 mmol). H NMR (500
MHz, CDCl3) δ 7.29-7.22 (m, 2H), 7.20-7.12 (m, 3H), 3.26 (ddd,
J = 13.73, 10.38, 5.49 Hz, 1H), 3.01 (ddd, J = 13.73, 10.38, 5.49
Hz, 1H), 2.70-2.56 (m, 2H), 2.48 (sext, J = 7.32 Hz, 1H), 2.09
(dd, J = 12.21, 8.54 Hz, 1H), 1.75-1.99 (m, 2H), 1.40 (dd, J =
12.21, 10.07 Hz, 1H), 1.21 (s, 3H), 1.17 (d, J = 7.02 Hz, 3H), 1.11
(s, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 176.7, 141.5,
128.2, 128.2, 125.7, 58.4, 43.5, 39.3, 35.0, 33.5, 31.1, 28.4, 25.8,
16.3 ppm. IR (neat) ν 2964, 1681, 1455, 1371 cm-1. HRMS
(DART) calcd for C16H24O1N1 [M+H]+: 246.1857, found:
25
= ‒25.0 (c = 0.675, CHCl3). The ee value was determined by
D
chiral HPLC analysis, Column (CHIRALPAK IF-3), UV detector
220 nm, eluent: Hex/IPA = 20/1, Flow late = 1.0 mL/min, tR = 15
min (major product), tR = 16 min (minor product).
1-(tert-butyl)-3-methyl-4-phenylazetidin-2-one (25a)
O
N
25
246.1858. [α] D = ‒15.5 (c = 1.440, CHCl3). The ee value was
determined by chiral HPLC analysis, Column (CHIRALPAK IF-
3), UV detector 230 nm, eluent: Hex/IPA = 50/1, Flow late = 1.0
mL/min, tR = 44 min (major product), tR = 54 min (minor
product).
This compound was prepared according to the typical procedure
for asymmetric intramolecular C‒H insertion reaction of
diazoacetamide 23a (48.5 mg, 0.2 mmol, 1 equiv.) in the presence
of p-MeO-Ru(II)-Pheox (6.0 mg, 0.01 mmol, 5 mol%). The
resulting mixture was purified by column chromatography using
aluminium oxide with Hexane/EtOAc = 5/1 to give 1-(tert-butyl)-
3-methyl-4-phenylazetidin-2-one 25a as a white solid (85% yield,
1-(3-(4-methoxyphenyl)propyl)-3,5,5-trimethylpyrrolidin-2-
one (24f)
O
1
48.5 mg, 0.17 mmol). H NMR (500 MHz, CDCl3) δ 7.39-7.33

N
(m, 2H), 7.33-7.27 (m, 3H), 4.77 (d, J = 5.7 Hz, 1H), 3.34 (dq, J =
7.5, 5.7 Hz, 1H), 1.30 (s, 9H), 0.78 (d, J = 7.6 Hz, 3H) ppm.
13C{1H} NMR (125 MHz, CDCl3) δ 171.6, 138.3, 128.4, 127.9,
127.5, 58.0, 54.2, 48.2, 28.2, 9.7 ppm. The ee value was
determined by chiral HPLC analysis, Column (CHIRALPAK IE-
3), UV detector 230 nm, eluent: Hex/IPA = 20/1, Flow late = 1.0
MeO
This compound was prepared according to the typical procedure
for asymmetric intramolecular C‒H insertion reaction of α-
diazoacetamide 23f (60.0 mg, 0.198 mmol, 1.0 equiv.) in the
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The Journal of Organic Chemistry
Page 12 of 14
intermolecular C–H functionalization by donor/acceptor rhodium
mL/min. Major product (7% ee): tR = 10.5 min, tR = 12.8 min.
Minor product (43% ee): tR = 11.4 min, tR = 14.1 min.
carbenes. Chem. Soc. Rev. 2011, 40, 1857. (c) Yamaguchi, J.; Yamaguchi
D. A.; Itami, K. C‒H Bond Functionalization: Emerging Synthetic Tools
for Natural Products and Pharmaceuticals. Angew. Chem., Int. Ed. 2012,
51, 8960.
1
2
3
4
5
6
7
8
1-(tert-butyl)-4-phenyl-3-(phenylsulfonyl)pyrrolidin-2-one
(25d)5j
(2) (a) Doyle, P. M.; Protopopova, N. M.: Winchester, R. W.; Daniel, L.
K. Enantiocontrol and regiocontrol in lactam syntheses by intramolecular
carbon-hydrogen insertion reactions of diazoacetamides catalyzed by
chiral rhodium(II). Tetrahedron Lett. 1992, 33, 7819. (b) Padwa, A.;
Austin, J. D.; Price, A. T.; Semones, A. M.; Doyle, P. M. Protopopova, N.
M.; Winchester, R. W.; Tran, A. Ligand effects on dirhodium(II) carbene
reactivities. Highly effective switching between competitive carbenoid
transformations. J. Am. Chem. Soc., 1993, 115, 8669. (c) Brown, S. D.;
Elliott, C. M.; Moody, J. C.; Mowlem, J. T.; Marino, P. J., Jr.; Padwa, A.
Ligand Effects in the Rhodium(II)-Catalyzed Reactions of .alpha.-
Diazoamides. Oxindole Formation is Promoted by the Use of Rhodium(II)
Perfluorocarboxamide Catalysts. J. Org. Chem. 1994, 59, 2447. (d)
O
O
S
O
N
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This compound was prepared according to the typical procedure
for asymmetric intramolecular C‒H insertion reaction of
diazoacetamide 23d (77.8 mg, 0.2 mmol, 1 equiv.) in the presence
of p-MeO-Ru(II)-Pheox (6.0 mg, 0.01 mmol, 5 mol%). The
resulting mixture was purified by column chromatography using
aluminium oxide with Hexane/EtOAc = 5/1 to give 1-(tert-butyl)-
4-phenyl-3-(phenylsulfonyl)pyrrolidin-2-one 25d as a colorless
oil (93% yield, 63.9 mg, 0.17 mmol, racemic). 1H NMR (500
MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz,2H), 7.65 (t, J = 7.3 Hz, 1H),
7.54 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.27 (t, J = 7.1
Hz, 1H), 7.20 (d, J = 6.9 Hz, 2H), 4.11 (dt, J = 5.2, 2.5 Hz, 1H),
4.04 (dd, J = 9.7, 8.2 Hz, 1H), 3.87 (d, J = 2.7 Hz, 1H), 3.52 (dd,
J = 9.7, 2.1 Hz, 1H), 1.43 (s, 9H) ppm. 13C{1H} NMR (125 MHz,
CDCl3) δ 164.9, 142.4, 137.8, 134.1, 129.9, 129.3, 127.8, 126.4,
75.0, 55.3, 51.9, 37.0, 27.3 ppm. The ee value was determined by
chiral HPLC analysis, Column (CHIRALPAK OJ-H), UV
detector 230 nm, eluent: Hex/IPA = 20/1, Flow late = 1.0
mL/min, tR = 12.3 min (major product), tR = 21.1 min (minor
product).
Padwa, A.; Straub, S. C. Synthesis of Furo[3,4-c]furans Using
a
Rhodium(II)-Catalyzed Cyclization/Diels−Alder Cycloaddition Sequence.
J. Org. Chem. 2003, 68, 227. (e) Thu, H.-Y.; Tong, S.-M. G.; Huang, J.-
S.; Chan, L.-F. S.; Deng, Q.-H.; Che, C.-M. Innentitelbild: Highly
Selective Metal Catalysts for Intermolecular Carbenoid Insertion into
Primary C‒H Bonds and Enantioselective C‒C Bond Formation. Angew.
Chem. 2008, 120, 9893. (f) Qin, C.; Davies, H. M. L. Role of Sterically
Demanding Chiral Dirhodium Catalysts in Site-Selective C–H
Functionalization of Activated Primary C–H Bonds. J. Am. Chem. Soc.
2014, 136, 9792. (g) Guptill, M. D.; Davies, H. M. L. 2,2,2-Trichloroethyl
Aryldiazoacetates as Robust Reagents for the Enantioselective C–H
Functionalization of Methyl Ethers. J. Am. Chem. Soc. 2014, 136, 17718.
(h) Hashimoto, T.; Yamamoto, K.; Maruoka, K. Catalytic enantioselective
intramolecular cyclization of N-aryl diazoamides using a titanium–
BINOLate complex. Chem. Commun. 2014, 50, 3220. (i) Liao, K.;
Negretti, S.; Musaev, G. D.; Bacsa, J.; Davies, H. M. L. Site-selective and
stereoselective functionalization of unactivated C–H bonds. Nature 2016,
533, 230. (j) Fu, L.; Guptill, M. D.; Davies, H. M. L. Rhodium(II)-
Catalyzed C–H Functionalization of Electron-Deficient Methyl Groups. J.
Am. Chem. Soc. 2016, 138, 5761. (k) Nakayama, H.; Harada, S.; Kono,
M.; Nemoto, T. Chemoselective Asymmetric Intramolecular
Dearomatization of Phenols with α-Diazoacetamides Catalyzed by Silver
Phosphate. J. Am. Chem. Soc. 2017, 139, 10188. (l) Wang, Y.; Wen, X.;
Cui, X.; Zhang, X. P. Enantioselective Radical Cyclization for
Construction of 5-Membered Ring Structures by Metalloradical C–H
Alkylation. J. Am. Chem. Soc. 2018, 140, 4792.
(3) (a) Chanthamath, S.; Iwasa, S. Enantioselective Cyclopropanation of a
Wide Variety of Olefins Catalyzed by Ru(II)–Pheox Complexes. Acc.
Chem. Res. 2016, 49, 2080. (b) Mandour, A. S. H.; Chanthamath, S.;
Shibatomi, K.; Iwasa, S. Inter- and Intramolecular Cyclopropanations of
Diazo Weinreb Amides Catalyzed by Ruthenium(II)-Amm-Pheox. Adv.
Synth, Catal. 2017, 359, 1742. (c) Kotozaki, M.; Chanthamath, S.;
Fujisawa, I.; Shibatomi, K.; Iwasa, S. Highly stereoselective
cyclopropanation of various olefins with diazosulfones catalyzed by
Ru(II)–Pheox complexes. Chem. Commun. 2017, 53, 12193. (d) Kotozaki,
M.; Chanthamath, S.; Fujii, T.; Shibatomi, K.; Iwasa, S. Highly
enantioselective synthesis of trifluoromethyl cyclopropanes by using
Ru(II)–Pheox catalysts. Chem. Commun. 2018, 54, 5110. (e) Nakagawa,
Y.; Imokawa, Y.; Fujisawa, I.; Nakayama, N.; Goto, H.; Chanthamath, S.;
Shibatomi, K.; Iwasa, S. Ligand Exchange Reaction on a Ru(II)–Pheox
Complex as a Mechanistic Study of Catalytic Reactions. ACS Omega
2018, 3, 11286. (f) Tone, M.; Nakagawa, Y.; Chanthamath, S.; Fujisawa,
ASSOCIATED CONTENT
Supporting Information
Characterization data: 1H and 13C NMR spectra, high-
performance liquid chromatography data. The Supporting
Information is available free of charge on the ACS Publications
website.
AUTHOR INFORMATION
Corresponding Author
Soda Chanthamath: soda@elabtube.com
Seiji Iwasa: iwasa@ens.tut.ac.jp
Author Contributions
These authors contributed equally.
Notes
The authors declare no competing financial interests.
I.; Nakayama, N.; Goto, H.; Shibatomi, K.; Iwasa, S.
A Highly
Stereoselective Spirocyclopropanation of Various Diazooxindoles with
Olefines Catalyzed by Ru(II)-Complex. RSC Advances, 2018, 8, 39865.
(g) Nakagawa, Y.; Nakayama, N.; Goto, H.; Fujisawa, I.; Chanthamath,
S.; Shibatomi, K.; Iwasa, S. Computational Chemical Analysis of Ru(II)-
ACKNOWLEDGMENT
Pheox
Catalyzed
Highly
Enantioselective
Intramolecular
This work was supported by a Grant-in-Aid for Scientific
Research (B) (No. 26288087), Ikeda Bussan Co. Letd., and Grant-
in-Aid for JSPS Research Fellow (No. 16J06159) from Japan
Society for the Promotion of Science.
Cyclopropanation Reactions. Chirality, 2019, 31, 52–61.
(4) (a) Chanthamath, S.; Thongjareun, S.; Shibatomi, K.; Iwasa, S. Ru(II)-
Pheox catalyzed N–H insertion reaction of diazoacetamides: synthesis of
N-substituted α-aminoamides. Tetrahedron Lett. 2012, 53, 4862. (b)
Nakagawa, Y.; Chanthamath, S.; Fujisawa, I.; Shibatomi, K.; Iwasa, S.
Ru(II)-Pheox-catalyzed Si–H insertion reaction: construction of
enantioenriched carbon and silicon centers. Chem. Commun. 2017, 53,
3753.
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The Journal of Organic Chemistry
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up to 95%
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9
(9) Mo, S.; Xu, J. Chemospecific Intramolecular Buchner Reaction
Catalyzed by Copper(II) Acetylacetonate. Chem. Cat. Chem. 2014, 6,
1679.
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synthesis
by
intramolecular
C–H
functionalization
from
enoldiazoacetamides and derivative donor–acceptor cyclopropenes. Chem.
Sci. 2015, 6, 2196.
(6) Lo, K.-Y. V.; Guo, Z.; Choi, K.-W. M.; Yu, W.-Y.; Huang, J.-S.; Che,
C.-M. Highly Selective Intramolecular Carbene Insertion into Primary C–
H Bond of α-Diazoacetamides Mediated by a (p-Cymene)ruthenium(II)
Carboxylate Complex. J. Am. Chem. Soc. 2012, 134, 7588.
(7) A copper catalyzed intramolecular C‒H insertion reaction of both
diazoacetamide and diazoester (such as (CH3CH2)2NC(O)CHN2) has been
reported. See: Martín, C. Belderraín, T. R.; Pérez, P. Rediscovering
copper-based catalysts for intramolecular carbon–hydrogen bond
functionalization by carbene insertion. J. Org. Biomol. Chem. 2009, 7,
4777.
(8) Intramolecular C‒H insertion reaction using diazoacetamide 7f had
investigated by rhodium catalysts (Rh2L4
= Rh2(OAc)4, Rh2(pfb)4,
Rh2(cap)4, Rh2(acam)4) (ref. 2 (a)), the carbene insertion reaction into
secondary C‒H and aromatic cycloaddition proceeded selectively.
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