Synthesis of γ-lactams via Ru(II)–Pheox-catalyzed regioselective intramolecular Csp3–H insertion of diazoacetamides

Article abstract of DOI:10.1016/j.tetlet.2020.152276

Herein, γ-lactam derivatives are obtained in high yield via highly regioselective intramolecular Csp³–H insertion reactions of α-diazoacetamides catalyzed by a rac-Ru(II)–Pheox complex. The catalytic system is applicable to a wide range of diaz

Full text of DOI:10.1016/j.tetlet.2020.152276

Journal Pre-proofs
Synthesis of γ-lactams via Ru(II)–Pheox-catalyzed regioselective intramolec‐
ular Csp3 –H insertion of diazoacetamides
Takuji Fujii, Huong Dang Thi Thu, Seiji Iwasa
PII:
S0040-4039(20)30743-7
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152276
TETL 152276
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 May 2020
17 July 2020
20 July 2020
Please cite this article as: Fujii, T., Thu, H.D.T., Iwasa, S., Synthesis of γ-lactams via Ru(II)–Pheox-catalyzed
regioselective intramolecular Csp3 –H insertion of diazoacetamides, Tetrahedron Letters (2020), doi: https://
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Synthesis of γ-lactams via Ru(II)–Pheox-
catalyzed regioselective intramolecular
Csp3–H insertion of diazoacetamides
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Takuji Fujii, Huong Dang Thi Thu, and Seiji Iwasa*

1
Tetrahedron Letters
Synthesis of γ-lactams via Ru(II)–Pheox-catalyzed regioselective intramolecular
Csp3–H insertion of diazoacetamides
Takuji Fujii, Huong Dang Thi Thu, and Seiji Iwasa 
Department of Applied Chemistry and Life Science, Toyohashi University of Technology, Tempaku-cho, Toyohashi-shi, Aichi 441-8580, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein, γ-lactam derivatives are obtained in high yield via highly regioselective intramolecular
Csp3–H insertion reactions of α-diazoacetamides catalyzed by a rac-Ru(II)–Pheox complex. The
catalytic system is applicable to a wide range of diazoacetamides under mild conditions to produce
the corresponding γ-lactams.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
C–H Insertion
γ-Lactam
Ruthenium
Carbene
Diazoacetamide
γ-Lactam ring is frequently an important building block of
numerous biologically active compounds, including natural
products and pharmaceuticals [1]. Although its synthetic
approaches, such as the cyclization of amino acids [2],
intramolecular N-alkylation [3], and formal [3+2] annulations
[4], have been commonly used for more than a hundred years,
transition-metal-catalyzed reactions have recently offered
opportunities to access this important heterocyclic motif [5].
In our previous studies, we have demonstrated that Ru(II)–
Pheox complexes are highly efficient catalysts for carbene
transfer reactions, such as asymmetric cyclopropanation, and
N–H and Si–H insertion reactions [12]. Recently, we
successfully reported a highly regio- and enantioselective
intramolecular carbene insertion reaction into a primary
Csp3–H bond of a tert-butyl group (Scheme 1a) and an
inactive aromatic ring of a benzyl group (Büchner ring
expansion) to produce the corresponding γ-lactam derivatives
with diazoacetamides [12g,h]. Herein, we report that Ru(II)–
Among
the
reported
metal-catalyzed
methods,
intramolecular carbene C–H insertion reactions of
diazoacetamides have attracted significant research attention
for the preparation of lactam derivatives [6]. However, this
methodology has not been extensively investigated for
cyclization, because of the difficulty in controlling the
chemo- and regioselectivities. Moreover, mono-substituted
diazoacetamides are less commonly used than di-substituted
diazoacetamides, diazoesters, and diazoketones. The extent
of side reactions is determined by the catalyst and the
nitrogen-protecting group. Although several nitrogen-
protecting groups such as N-tert-butyl [7], N-benzyl [8], N-
bis(trimethylsilyl)-methyl
[9],
and
N-(2,3,4,5,6-
pentafluorobenzyloxy) [10] have been proposed, effective
catalysts for regioselective intramolecular carbene C–H
insertion reactions have not been widely investigated [11].
Therefore, for highly selective intramolecular C–H insertion
reactions of diazoacetamides, new metal catalysts that present
reactivity profiles complimentary to those of existing catalyst
families are required.
Scheme 1. Ru(II)–Pheox-catalyzed regioselective Csp3–H insertion
reaction.
———
 Corresponding author. E-mail: iwasa@ens.tut.ac.jp

2
entries 5 and 6), further investigation using rac-Ru(II)–Pheox
catalyst was conducted in order to find a suitable catalytic system
for the general synthesis of rac-γ-lactams.
Pheox, an efficient ruthenium catalyst containing a metal–
carbon bond, catalyzes the intramolecular carbene insertion
reaction into the Csp3–H bonds of diazoacetamides to
produce a broad range of γ-lactam derivatives in good to high
yield under mild conditions (Scheme 1b).
To further examine the influence of other factors, reaction
optimization studies were performed using a range of solvents,
temperatures, and Ru(II)–Pheox catalyst loadings (Table 2).
The solvent screening indicated that dichloromethane
produced a higher yield than acetone, THF, diethyl ether, and
toluene (Table 2, entries 1–5). The reaction temperatures
were also examined, and the yield decreased leaving the
unreacted substrate when the reactions were cooled to below
room temperature (Table 2, entries 6 and 7). It was found that
heat energy at room temperature is required for this Csp3–H
insertion reaction to fully proceed. Lowering the catalyst
loading amount from 1.0 to 0.5 mol% caused a significant
decrease in the yield, whereas the increased loading (0.5–2.0
Initially, we tested the intramolecular insertion reaction of N-
cyclopentyl-2-diazo-N-methylacetamide 1, as an amide carbene
precursor, under our previously described reaction condition for
the ruthenium-catalyzed functionalization of primary C–H bonds
of diazoacetamides (1.0 mol% of cat. Ru(II)–Pheox, CH2Cl2, room
temperature) [12g]. Unexpectedly, the reaction catalyzed by
Ru(II)–Pheox proceeded rapidly to furnish 2 in 94% yield under
the mild condition (Table 1, entry 1). To further investigate the
activity and selectivity of other metals that are well-known
catalysts for carbene transfer reactions, subsequently, we applied
copper(I), ruthenium(II), and dirhodium(II) under the reaction
conditions (Table 1, entries 2–7). Consequently, the Ru(II)–Pheox
catalyst exhibited the optimal chemoselectivity for the selective
formation of the five-membered lactam ring among all the
considered metal catalysts. Copper catalysts such as CuI and
[Cu(R,R)-Ph-box](OTf) [13] resulted in low yield (Table 1, entries
2 and 5), whereas Rh2(OAc)4 and [Rh2(S-tbpttl)4] [14] generated
the desired product in moderate yields of 50 and 42%, respectively
(Table 1, entries 4 and 7). In contrast to the copper and rhodium
catalysts, other ruthenium complexes [15] as catalysts (Table 1,
entries 3 and 6) did not afford lactam 2. Although asymmetric
catalyst 3 and 6 showed 9 and 37% ee of 2 respectively (Table 1,
mol%) of Ru(II)–Pheox afforded the highest yield
2 at 1.0
mol% of the catalyst (Table 2, entries 8 and 9).
To explore the scope of this reaction, a series of amide N-
substituents were subsequently investigated under the optimized
condition. As demonstrated by the data in Table 3, all N-
cyclopentyl diazoacetamides could be efficiently converted to the
corresponding γ-lactams in good to high yields. Interestingly, even
when the N-cyclopentyl diazoacetamides possessed alkyl groups,
including secondary and tertiary Csp3–H bonds, insertion of the
reactive carbene into the C–H bond of the cyclopentyl group
proceeded preferentially (Table 3, 8a–c). When 7b was used as the
a
Table 1. Screening of various metal catalysts
.
Entry
Catalyst
Time [min]
Yield of 2 [%]
1
2
3
4
5
6
7
rac-Ru(II)–Pheox
CuI
10
10
94
25
0
[(benzene)RuCl2]2
10
Rh2(OAc)4
120
90
50
19
0
[Cu(R,R)-Ph-box)](OTf) 3
(R,R)-iPr-pybox 4 + [(p-cymene)RuCl2]2 5
[Rh2(S-tbpttl)4] 6
10
10
42
a General conditions: A solution of N-cyclopentyl-2-diazo-N-methylacetamide 1 in CH2Cl2 was added dropwise to a solution of the catalyst (1.0
mol%) in CH2Cl2 at RT. b Isolated yield.
a
Table 2. Optimization of reaction conditions
.
Entry
Loading [X mol%]
Solvent
Temp. [°C]
Time [min]
Yield of 2 [%]
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
2.0
CH2Cl2
Acetone
THF
RT
RT
RT
RT
RT
0
10
10
94
24
49
65
12
85
17
60
96
10
Et2O
120
90
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
–10
RT
RT
2 days
10
1
a General conditions: A solution of N-cyclopentyl-2-diazo-N-methylacetamide 1 in each of the solvents was added dropwise to a solution of the
Ru(II)–Pheox in each of the solvents. b Isolated yield.

3
a,b
Table 3. Scope of various N-substituents
.
Scheme 2. Reaction of a secondary diazoacetamide and a
diazoester.
reactions of diazoacetamides, 11a and 11b, presented
excellent regioselectivities with cyclohexyl and cycloheptyl
groups, whereas these trans-isomers were also formed with
low diastereoselectivities of trans:cis = 33:67 (12a) and 27:73
(
12b), respectively. When cyclopentyl and cyclohexyl groups
containing an aromatic ring were used as the reactive sites,
the carbene insertion reactions into the ArCsp2–H bonds and
Büchner ring expansion reaction did not occur under the
optimized conditions. Therefore, these substrates were
converted to cis-γ-lactams, 12c and 12d in high yield. The
substrates with a long carbon chain resulted in good yield for
12e. Although the reaction of 11f was ineffective under the
optimized conditions, it proceeded rapidly in the presence of
3.0 mol% of the Ru(II)–Pheox catalyst at 40 °C to produce
12f in a good yield. In contrast, a similar substrate, 11g, was
smoothly converted to 12g in 79% yield at room temperature.
These results suggested that a tertiary C–H bond is more
reactive than a secondary one. In addition, spiro-fused γ-
lactam 12h was also obtained in a high yield via the selective
carbene insertion reaction. The Csp3–H bond adjacent to a
Boc-protected nitrogen bond was also transformed into the
substrate, increasing the catalyst loading from 1.0 to 3.0 mol%
resulted in complete conversion and produced 8b in 96% yield.
When 7d, 7e, and 7f possessing a benzyl group were used as
substrates, intramolecular Büchner ring expansions [12h,16] and
insertion reactions into the benzylic ring of C–H bonds [17] also
occurred. The ratios of the compounds were determined by the
corresponding C–C bond to produce γ-lactam 12i
.
Table 4. Substrate scope a,b
.
1
integration of the characteristic H-nuclear magnetic resonance
(NMR) absorptions from the spectra of the crude reaction mixtures.
Compared to 7f and 7d, 7e, having an more electron-rich benzyl
group, promoted the production of the seven-membered ring as the
sole side reaction, and the γ-lactam 8e was obtained in 39% yield.
The regioselectivity of the carbene transfer reaction for 7g, which
has a nitro group as the strong electron-withdrawing group,
dramatically increased, producing only the desired γ-lactam 8g in
96% yield. In addition, the ortho-chloro-substituted benzyl group
was found to realize the highest regioselectivity of the reaction,
and 8h was obtained in 99% yield. In addition to the alkyl and
benzyl groups, N-alkoxy diazoacetamide 7i was selectively
converted to the corresponding γ-lactam 8i in 95% yield.
Furthermore, the effects of a secondary amide and an ester
were tested, as depicted in Scheme 2. However, N-
cyclopentyl diazoacetamide
9 and cyclopentyl diazoacetate
10 [18] generated only dimers of the carbene. These results
suggested that the N-substituents of the amides are necessary
to hold the active site of the carbenoids close to the
intramolecular C–H bonds.
Subsequently, the scope of various N-methyl
diazoacetamides was also investigated (Table 4.) The

4
Tetrahedron Letters
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complex to form a ruthenium carbene complex,
Subsequently, a C–H bond reacts with the reactive site of the
intermediate, , resulting in the formation of . Finally, the
reductive elimination of ruthenium produces with the
concurrent regeneration of the Ru(II)–Pheox catalyst.
1
is reduced by the Ru(II)–Pheox
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In summary, we developed an efficient method for the synthesis
of γ-lactams by the intramolecular Csp3–H insertion reaction
catalyzed by a Ru(II)–Pheox complex. Various γ-lactams were
successfully synthesized in moderate to high yield under mild
conditions. The Ru(II)–Pheox catalyst presented higher chemo-
and regioselectivities for the synthesis of the γ-lactam derivatives
than the conventional metal catalysts. The development of other
transformations and asymmetric versions is currently being
investigated in our laboratory.
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This work was supported by a Grant-in-Aid for Scientific
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