Enantioselective Ring-Closing C–H Amination of Urea Derivatives

Article abstract of DOI:10.1016/j.chempr.2020.05.017

An enantioselective intramolecular C(sp³)–H amination of N-benzoyloxyurea by using a chiral-at-metal ruthenium catalyst is reported, providing chiral 2-imidazolidinones in yields of up to 99percent and with up to 99percent ee. Catalyst loadings down to 0.05 mol percent are feasible. Control experiments support a stepwise nitrene insertion mechanism through hydrogen atom transfer of a ruthenium nitrenoid intermediate followed by a radical recombination. Chiral 2-imidazolidinones are prevalent in bioactive compounds and can be converted to chiral vicinal diamines in a single step. The synthetic value of the new method is demonstrated for the synthesis of intermediates of the drugs levamisole and dexamisole, the bisindole alkaloids topsentine D and spongotine A, and a chiral organocatalyst. Direct C–H functionalization offers the prospect for streamlined synthesis with high atom economy. In this respect, the transition-metal-catalyzed enantioselective insertion of nitrenoids into prochiral sp³ C–H bonds is a powerful tool for the efficient construction of non-racemic chiral nitrogen-containing molecules. Intramolecular versions have been used to synthesize chiral nitrogen heterocycles, but cyclic urea is still elusive through enantioselective nitrenoid insertion chemistry. Here, we fill this gap and report an enantioselective intramolecular C(sp³)–H amination of N-benzoyloxyurea to provide chiral 2-imidazolidinones in high yields and with high enantioselectivities. The synthetic utility of this new method is illustrated with the catalytic asymmetric synthesis of medicinal agents, natural products, and a chiral organocatalyst. Our work emphasizes the usefulness of transition-metal-controlled asymmetric nitrene chemistry and the importance of tailored catalyst design. Here, we report the first catalytic asymmetric ring-closing C(sp³)–H amination of urea derivatives to construct chiral 2-imidazolidinones, which are prevalent in bioactive compounds and can be converted to chiral vicinal diamines. The simple and mild transformation is catalyzed by a recently developed chiral-at-ruthenium complex in high yields and with high enantioselectivities. Applications to the drugs levamisole and dexamisole, the bisindole alkaloids topsentine D and spongotine A, and a chiral organocatalyst demonstrate the synthetic value of this new method.

Full text of DOI:10.1016/j.chempr.2020.05.017

ll
Article
Enantioselective Ring-Closing C–H Amination
of Urea Derivatives
Zijun Zhou, Yuqi Tan, Tatsuya
Yamahira, ..., Marcel Hemming,
Masanari Kimura, Eric Meggers
meggers@chemie.uni-marburg.de
HIGHLIGHTS
First enantioselective ring-closing
C(sp3)–H amination of urea
derivatives
Simple access to chiral 2-
imidazolidinones which can be
converted to vicinal diamines
Applications to the synthesis of
pharmaceuticals, natural
products, and a chiral catalyst
Chiral-at-metal catalyst used in
challenging asymmetric nitrenoid
insertion chemistry
Here, we report the first catalytic asymmetric ring-closing C(sp3)–H amination of
urea derivatives to construct chiral 2-imidazolidinones, which are prevalent in
bioactive compounds and can be converted to chiral vicinal diamines. The simple
and mild transformation is catalyzed by a recently developed chiral-at-ruthenium
complex in high yields and with high enantioselectivities. Applications to the drugs
levamisole and dexamisole, the bisindole alkaloids topsentine D and spongotine
A, and a chiral organocatalyst demonstrate the synthetic value of this new method.
Zhou et al., Chem 6, 1–11
August 6, 2020 ª 2020 Elsevier Inc.
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Article
Enantioselective Ring-Closing C–H
Amination of Urea Derivatives
Zijun Zhou,1 Yuqi Tan,1 Tatsuya Yamahira,2 Sergei Ivlev,1 Xiulan Xie,1 Radostan Riedel,1
Marcel Hemming,1 Masanari Kimura,2 and Eric Meggers1,3,
*
SUMMARY
The Bigger Picture
An enantioselective intramolecular C(sp3)–H amination of N-ben-
zoyloxyurea by using a chiral-at-metal ruthenium catalyst is re-
ported, providing chiral 2-imidazolidinones in yields of up to 99%
and with up to 99% ee. Catalyst loadings down to 0.05 mol % are
feasible. Control experiments support a stepwise nitrene insertion
mechanism through hydrogen atom transfer of a ruthenium nitre-
noid intermediate followed by a radical recombination. Chiral 2-imi-
dazolidinones are prevalent in bioactive compounds and can be con-
verted to chiral vicinal diamines in a single step. The synthetic value
of the new method is demonstrated for the synthesis of intermedi-
ates of the drugs levamisole and dexamisole, the bisindole alkaloids
topsentine D and spongotine A, and a chiral organocatalyst.
Direct C–H functionalization offers
the prospect for streamlined
synthesis with high atom
economy. In this respect, the
transition-metal-catalyzed
enantioselective insertion of
nitrenoids into prochiral sp3 C–H
bonds is a powerful tool for the
efficient construction of non-
racemic chiral nitrogen-
containing molecules.
Intramolecular versions have been
used to synthesize chiral nitrogen
heterocycles, but cyclic urea is still
elusive through enantioselective
nitrenoid insertion chemistry.
Here, we fill this gap and report an
enantioselective intramolecular
C(sp3)–H amination of N-
INTRODUCTION
The direct catalytic asymmetric conversion of prochiral C(sp3)–H into C–N bonds of-
fers an efficient synthetic route to non-racemic chiral nitrogen-containing mole-
cules.1–3 In one mechanistic manifold, intermediate transition metal nitrenoids insert
a nitrogen atom between C–H bonds in either a stepwise or concerted fashion (Figure
1A).4–8 A variety of functional groups serving as nitrene precursors have been devel-
oped and the intramolecular version of the reaction renders directing groups obso-
lete while exerting high control over the regioselectivity. This has been applied to the
catalytic asymmetric synthesis of cyclic sulfamidates,9–11 sulfamides,12–14 sulfon-
amides,15–18 carbamates,19,20 lactams,21–24 Boc-protected pyrrolidines,25,26 and
related Boc-protected heterocycles (Figure 1B).27 However, interestingly, urea deriv-
atives as nitrene precursors leading to chiral cyclic urea, specifically 2-imidazolidi-
nones, are absent from this list.28 This is unfortunate considering the prevalence of
chiral 2-imidazolidinones in bioactive compounds and their use as chiral auxil-
iaries.29,30 Furthermore, chiral 2-imidazolidinones can be converted in a single step
to chiral vicinal diamines, which are valuable building blocks for the synthesis of me-
dicinal agents, natural products, chiral ligands, and chiral catalysts.31–33
benzoyloxyurea to provide chiral
2-imidazolidinones in high yields
and with high enantioselectivities.
The synthetic utility of this new
method is illustrated with the
catalytic asymmetric synthesis of
medicinal agents, natural
products, and a chiral
organocatalyst. Our work
emphasizes the usefulness of
transition-metal-controlled
asymmetric nitrene chemistry and
the importance of tailored catalyst
design.
Here, we report an intramolecular asymmetric C(sp3)–H amination of N-benzoylox-
yurea (Figure 1C). The enantioselective cyclization is highly efficient with catalyst load-
ings down to 0.05 mol %. To our knowledge, this is the first example of chiral cyclic urea
synthesized through a catalytic enantioselective nitrene C–H insertion strategy.
RESULTS AND DISCUSSION
Initial experiments and optimization
We recently disclosed enantioselective nitrene insertion chemistry of organic
azides and 1,4,2-dioxazol-5-ones by using ‘‘chiral-at-metal’’ ruthenium catalysts
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1

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A
B
C
Figure 1. Enantioselective Intramolecular Amination of Prochiral C(sp3)–H Bonds
(A) Transition metal nitrene intermediates.
(B) Chiral heterocycles accessible by this strategy.
(C) Method developed in this report.
with exclusive metal-centered chirality (only achiral ligands).24,26,27 We anticipated
that this novel class of catalysts would allow us to address the challenge of access-
ing chiral 2-imidazolidinones by enantioselective C(sp3)–H amination from judi-
ciously chosen urea derivatives. We initiated our study with the N-benzoyloxyurea
1aa (see Scheme S1 for substrate preparation) and envisioned that after release of
1Fachbereich Chemie, Philipps-Universitat
¨
Marburg, Hans-Meerwein-Strasse 4, 35043
Marburg, Germany
the benzoate leaving group, an intermediate ruthenium nitrenoid would form and
engage in an intramolecular C–H amination.34 Indeed, in the presence of 1 mol %
2Division of Chemistry and Materials Science,
Graduate School of Engineering, Nagasaki
University, 1-14 Bunkyo-machi, Nagasaki
852-8521, Japan
ruthenium catalyst (Ru1) and K2CO3 (3 equiv) in CH2Cl2 at room temperature for 16
h, the 2-imidazolidinone 2a was formed in quantitative yield and with 86% enantio-
meric excess (ee) (Table 1, entry 1). Optimization of the chiral-at-metal ruthenium
catalyst (Ru2–Ru5,26,27,35,36 entries 2–5) improved the enantioselectivity to 95% ee
by using the trimethylsilyl-modified ruthenium catalyst Ru5 (see Scheme S2 for
catalyst preparation). Functionalization of the benzoate leaving group with an elec-
tron-donating methoxy (1ab) (entry 6) or electron-withdrawing CF3-group (1ac)
3Lead Contact
*Correspondence:
meggers@chemie.uni-marburg.de
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Table 1. Evaluation of the C(sp3)–H Amination Reactiona
Entry
1
Catalysts
L-Ru1
L-Ru2
L-Ru3
L-Ru4
L-Ru5
L-Ru5
L-Ru5
L-Ru5
L-Ru5
L-Ru5
L-Ru5
L-Ru5
X
Conditionsa,b
Standard
Yield (%)c
100
ee (%)d
86
1aa
1aa
1aa
1aa
1aa
1ab
1ac
1ad
1aa
1aa
1aa
1aa
2
Standard
100
94
3
Standard
100
95
4
Standard
100
94
5
Standard
100 (99)e
100
95
6
Standard
94
7
Standard
100
94
8
Standard
27
91
9
0.5 mol % catalyst)
0.1 mol % catalystf
0.05 mol % catalystf
no baseg
100
94
10
11
12
100
94
66
93
100
94
aStandard conditions: Substrate 1aa–1ad (0.2 mmol), K2CO3 (0.6 mmol), Ru catalyst (0.002 mmol) in CH2Cl2 (2 mL) stirred at the indicated temperature for 16 h
under N2 unless noted otherwise.
bDeviations from standard conditions are shown.
cDetermined by 1H NMR of the crude products using Cl2CHCHCl2 as internal standard.
dEnantiomeric excess determined by HPLC analysis of the crude main product on a chiral stationary phase.
eIsolated yield in brackets.
fReaction executed at 40ꢀC for 24 h.
gIncreased reaction time of 48 h.
(entry 7) slightly affected the enantioselectivity. A pivaloate leaving group (1ad)
only provided the 2-imidazolidinone in 27% yield with 91% ee (entry 8). Interest-
ingly, the catalyst loading can be reduced down to 0.05 mol % upon increasing
the reaction time to 24 h and the temperature to 40ꢀC. (entries 9–11.) The addition
of a base is not required but increases the rate of reaction (entry 12) (see Table S1
for additional conditions).37
Mechanistic investigation
The proposed mechanism is shown in Figure 2. Upon release of benzoic acid from
the N-benzoyloxyurea, the ruthenium catalyst forms
a ruthenium nitrenoid
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Figure 2. Proposed Mechanism through an Intermediate Triplet Ruthenium Nitrenoid
intermediate (I). The ruthenium nitrenoid from its triplet state subsequently performs
a 1,5-hydrogen atom transfer (HAT) to provide the radical intermediate II. This is fol-
lowed by C–N bond formation through radical-radical recombination to provide the
ruthenium-coordinated product (III), which is released to regenerate the active cata-
lyst for a new catalytic cycle.
The radical mechanism is supported by a significant kinetic isotope effect (KIE) of
4.35, which we determined with an intramolecular competition experiment by us-
ing the deuterated substrate 1aa’ to provide the cyclized products 2a’ and 2a’’
with a ratio of 4.35:1 (Figures 3A and S1).38–41 The high KIE value obtained is a
strong indication for the formation of a triplet nitrene intermediate, which then en-
gages in radical chemistry. This is in contrast to our previous work on nitrene inser-
tion of 2-azidoacetamides in which a KIE value of 1.5 was determined by an anal-
ogous intramolecular competition experiment.27 The assumption that the
mechanism proceeds through intermediate radicals is further indicated by an
experiment performed with the diastereomeric substrates (Z)-1b and (E)-1b (Fig-
ures 3B and S2–S4). Whereas (E)-1b formed (E)-2b under complete retention of
the alkene configuration (80% yield, 76% ee), (Z)-1b (E:Z ratio > 20:1) was con-
verted to 2b with an eroded Z:E diastereomeric ratio of just 4.4:1 (73% yield,
91% ee). This can be rationalized with an isomerization from the thermodynami-
cally less stable Z-isomer to the preferred E-isomer in the course of the C–H ami-
nation at the stage of the allyl radical intermediate. However, the radical is appar-
ently short-lived so that no complete isomerization can occur. As expected, the
Z:E-ratio is temperature dependent with a higher Z:E-ratio at lower temperature
(5.1:1 at 4ꢀC) and a lower Z:E-ratio at higher temperature (2.9:1 at 40ꢀC). Finally,
a radical mechanism is also supported by the ring-closing C–H amination of the
chiral non-racemic substrate (S)-1c (89% ee) to provide (R)-2c under retention of
configuration for both catalyst enantiomers (Figure 3C). However, although the
D-catalyst provides (R)-2c with only slightly decreased enantioselectivity (85%
ee), the mismatched L-catalyst leads to a strong erosion of the enantiomeric
excess of (R)-2c (40% ee). This decrease in enantiomeric excess is not consistent
4
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A
B
C
Figure 3. Control Experiments to Probe the Proposed Radical Mechanism
(A) Kinetic isotope experiments.
(B) Olefin isomerization experiments.
(C) Stereochemical considerations.
with a concerted C–H insertion mechanism but rather indicates a radical pathway
in which the D-catalyst matches the S-configuration of the chiral substrate whereas
the L-catalyst constitutes a mismatch, thus resulting in a slower radical recombina-
tion and subsequent partial racemization.
Scope and Limitation
To explore the scope of this new method, we applied the reaction conditions to a
variety of N-benzoyloxyurea as shown in Figure 4. Benzylic C(sp3)–H aminations to
chiral 2-imidazolidinones occurred with high yields and high enantioselectivities.
For example, a para-, meta-, and even a sterically very hindering ortho-methyl
group in the phenyl moiety are well tolerated (products 2d–2f, 92%–99% yield,
95%–97% ee), as well as an electron-withdrawing fluorine (2g) and chlorine substit-
uent (2h, for crystallographic data see Table S2; Figure S34, CCDC number
1972573), and an electron-donating methoxy group (2i). A 1-naphthyl group pro-
vided the cyclic urea 2j with 99% yield and 99% ee, whereas a 2-naphthyl group
afforded the cyclic urea 2k with 97% yield and 90% ee. The smaller 2-thiophene
moiety provided the cyclic urea 2l with 99% yield but a somewhat reduced 88%
ee. We obtained 2-Imidazolidinone 2m with stereocenters in the 4- and 5-position
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Figure 4. Substrate Scope
aL-Ru4 was used as the catalyst instead.
in sluggish 29% yield but 89% ee by desymmetrization of an indane substrate by
using the ruthenium catalyst L-Ru4 instead of L-Ru5. However, the desymmetriza-
tion of a N-benzoyloxyurea derived from 1,3-diphenyl-2-propanamine provided
the 4,5-difunctionalized 2-imidazolidinones 2n with two adjacent stereocenters
as a single diastereomer in 93% yield with 94% ee (see Table S3; Figures S35–
S38 for the assignment of the relative configuration by NMR). Besides C(sp3)–H
aminations at benzylic and allylic positions (see Figure 3B), ring-closing C(sp3)–H
amination is also possible at a propargylic position in 89% yield and with 87%
ee (2o). However, methylene groups without any adjacent activation group do
not provide significant amounts of cyclization product (see Supplemental Informa-
tion for more details). The substrate was completely consumed but did not provide
any significant amount of useful product (e.g., 6-membered ring-close urea and ni-
trene reduction side-product).
The ring-closing C(sp3)–H amination to 2-imidazolidinones tolerates different
N-alkyl substituents as shown in Figure 5. Ethyl, n-butyl, isobutyl, and phenethyl
substituents are well tolerated providing the corresponding N-alkylated 2-imidazo-
lidinones 2p–2s in 68%–99% yield and with 92%–95% ee. However, a benzyl
substituents results in reduced yields of 37% yield for 2t (93% ee). Importantly,
the ring-closing C(sp3)–H amination is applicable to non-alkylated substrates
6
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Figure 5. Substrate Scope
Products 2p–2r formed with regioisomeric ratios of more than 20:1. a40 h reaction time. b16 h
reaction time.
as demonstrated with the product 2u containing two N–H groups which was
afforded in 91% yield and 91% ee. It is worth noting that a substrate bearing a
N-phenyl substituent (1v) only provided the corresponding C(sp2)–H amination
product (2v), which is not desired in this context but by itself a useful transformation.
Synthetic Applications
Chiral 2-imidazolidinones are highly valuable building blocks for the synthesis of
bioactive compounds, such as medicinal agents and natural products. For example,
(S)-4-phenyl-2-imidazolidinone [(S)-2u] can be obtained from the N-benzoyloxyurea
1u and just 0.2 mol % L-Ru5 in a yield of 74% with almost perfect enantioselectivity
of 99.6% ee after a single recrystallization step (Figure 6A). According to reported
procedures, this enantiomerically pure 2-imidazolidinone (S)-2u can be converted
to the drug levamisole42 by first thiation of the urea with Lawesson’s reagent43 fol-
lowed by cycloalkylation with 1,2-dibromoethane.44,45 Analogously, the drug dexa-
misole, which is the enantiomer of levamisole,46 can be synthesized from (R)-2u,
which we obtained from 1u by using D-Ru5 instead of L-Ru5.47–49
A second example provides a concise route to the bisindole alkaloids topsentine
D and spongotine A (Figure 6B). Accordingly, ring-closing C(sp3)–H amination of
the indole-containing substrates 1w and 1x provided, under standard conditions,
the 4-indolyl-2-imidazolidinones 2w and 2x, respectively, in high yields and with
high ee. These 2-imidazolidinones can be hydrolyzed with concentrated HCl in
AcOH at 85ꢀC under microwave conditions50 for 10 min to the respective vicinal
diamines 3a and 3b with almost unchanged enantiomeric excess and constitute in-
termediates of the natural products topsentine D51 and spongotine A,52 respec-
tively. A third example provides access to the mono-N-methylated 1,2-diamine
3c, which was reported as an intermediate for the synthesis of a chiral organocatalyst
(Figure 6C).53
Our method, introduced here, to access chiral vicinal diamines complements a cat-
alytic, enantioselective syn-diamination of alkenes to 1,3-ditosylimidazolidin-2-
ones recently reported by Denmark54 and related work by Mun˜ iz,55,56 but which
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A
B
C
Figure 6. Applications to the Synthesis of Medicinal Agents, Natural Products, and a Chiral
Organocatalyst
aStandard conditions followed by recrystallization in EtOAc:n-hexane. MW, microwave.
(A) Application to the synthesis of medicinal agents.
(B) Application to natural product synthesis.
(C) Application to the synthesis of a chiral catalyst.
all require the use of sulfonyl protection groups. Furthermore, Arnold recently re-
ported an enzymatic C(sp3)–H amination platform for the enantioselective synthesis
of cyclic sulfamides as building blocks for diverse chiral 1,2- and 1,3-diamines.14
Although the described method is very powerful, diamines with two primary
amines are apparently not accessible, and therefore, Arnold’s enzymatic method
through sulfamides is not suitable for the applications shown in Figure 6.
To conclude, here, we reported the first example of a ring-closing C(sp3)–H amination of
urea substrates to chiral 2-imidazolidinones in a catalytic enantioselective fashion. Start-
ing from abundant primary or secondary amines, N-benzoyloxyurea can be synthesized
in just two steps and enantioselectively cyclized to cyclic urea under mild reaction con-
ditions and by using low loadings of a chiral-at-metal ruthenium catalyst. We anticipate
that this method will be of significant synthetic interest because the furnished chiral
2-imidazolidinones and their corresponding chiral 1,2-diamines, obtained through effi-
cient hydrolysis with HCl, are highly valuable chiral building blocks.
EXPERIMENTAL PROCEDURES
Resource Availability
Lead Contact
Further information and requests for resources and reagents should be directed to
and will be fulfilled by the Lead Contact, Eric Meggers (meggers@chemie.uni-
marburg.de).
8
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Materials Availability
Unique and stable reagents generated in this study will be made available on
request, but we might require a payment and/or a completed materials transfer
agreement if there is potential for commercial application.
Data and Code Availability
The crystal structure data of compound (S)-2h has been deposited in the Cambridge
structural database under reference number 1972573.
Representative Method for Asymmetric C–H Amination Process
A dry Schlenk tube (10 mL) was charged with substrate 1aa (59.6 mg, 0.2 mmol), chi-
ral ruthenium catalyst Ru5 (0.002 mmol, 1.0 mol %), and K2CO3 (82.8 mg, 0.6 mmol)
under an atmosphere of N2. Freshly distilled dichloromethane (2.0 mL) was added
via syringe. The reaction mixture was stirred at ambient temperature for 16 h under
an atmosphere of N2. Thereafter, the mixture was transferred to a column and puri-
fied by flash chromatography on silica gel (EtOAc:n-hexane = 2:1 to EtOAc:MeOH
95:5) to afford the analytical pure product (S)-2a (34.9 mg, 99% yield) as a white solid.
An enantiomeric excess of 95% ee was determined by high performance liquid chro-
matography (HPLC) analysis on a chiral stationary phase (column: Daicel Chiralpak IA
250 3 4.6 mm, absorption: l = 220 nm, mobile phase: n-hexane:isopropanol =
90:10, flow rate: 1.0 mL/min, column temperature: 30ꢀC, retention times: tr (major) =
13.2 min, tr (minor) = 11.4 min).
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.05.017.
ACKNOWLEDGMENTS
E.M. is grateful for funding from the Deutsche Forschungsgemeinschaft, Germany
(ME 1805/15-1). M.K. is grateful for funding from the JSPS Program for Fostering
Globally Talented Researchers, Japan.
AUTHOR CONTRIBUTIONS
E.M. and M.K. coordinated the project; E.M. and Z.Z. wrote the manuscript with the help
of all co-authors; E.M. and Z.Z. conceived the project and designed the majority of the
experiments; Z.Z. carried out the majority of the experiments; Y.T., T.Y., and M.H.
contributed to the catalyst synthesis and synthesized some substrates; X.X. assigned
the relative configuration of product 2n by NMR experiments; S.I. and R.R. collected
the crystallographic data and solved and refined the X-ray crystal structure of 2h.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: April 2, 2020
Revised: May 8, 2020
Accepted: May 18, 2020
Published: June 23, 2020
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