Chemoselective Intramolecular Formal Insertion Reaction of Rh–Nitrenes into an Amide Bond Over C?H Insertion

Article abstract of DOI:10.1002/chem.201805878

The past few decades have witnessed extensive efforts to disclose the unique reactivity of metal–nitrenes, because they could be a powerful synthetic tool for introducing the amine functionality into unactivated chemical bonds. The reactivity of metal–nitrenes, however, is currently mainly confined to aziridination (an insertion into a C=C bond) and C?H amination (an insertion into a C?H bond). Nitrene insertion into an amide C?N bond, however, has not been reported so far. In this work we have developed a rhodium-catalyzed one-nitrogen insertion into amide C?N and sulfonamide S?N bonds. Experimental and theoretical analyses based on density functional theory indicate that the formal amide insertion proceeds via a rhodium-coordinated ammonium ylide formed between the nitrene and the amide nitrogen, followed by acyl group transfer concomitant with C?N bond cleavage. Mechanistic studies have allowed rationalization of the origin of the chemoselectivity observed between the C?H and amide insertion reactions. The methodology presented herein is the first example of an insertion of nitrene into amide bonds and provides facile access to unique diazacyclic systems with an N?N bond linkage.

Full text of DOI:10.1002/chem.201805878

A Journal of
Accepted Article
Title: Chemoselective Intramolecular Formal Insertion Reaction of Rh-
Nitrenes into an Amide Bond over C−H Insertion
Authors: Masato Kono, Shingo Harada, and Tetsuhiro Nemoto
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Chemoselective Intramolecular Formal Insertion Reaction of Rh-
Nitrenes into an Amide Bond over C−H Insertion
Masato Kono,[a] Shingo Harada,*,[a] and Tetsuhiro Nemoto*[a,b]
Dedication ((optional))
nitrene species and basic sp3 amines, and discovered sequential
Abstract: The past few decades have witnessed extensive efforts to
sigmatropic rearrangement followed by tosyl group transfer
disclose a unique reactivity of metal nitrenes since they could be a
10
]
(Scheme 1b).[
Despite these groundbreaking studies
powerful synthetic tool for introducing amine functionality into
unactivated chemical bonds. The reactivity of metal nitrenes,
however, is mainly confined to the aziridination (an insertion into a
C=C bond) and C−H amination (an insertion into a C−H bond). The
nitrene insertion into an amide C−N bond has not been reported so
showcasing the feasibility of ylide chemistry of metal-nitrenes,
no further investigations of other nucleophiles have been
reported except for nucleophilic sp2 or sp3 amines.[11]
Two specific issues might account for the insufficient
investigation of ylide chemistry involving metal-nitrenes. One is
that metal-nitrene species do not have a high electrophilic nature,
as elucidated by LUMO map analysis based on quantum
chemical calculation in our previous work.[12a,b] To compensate
for this, a high nucleophilicity is required to interact with the
metal nitrene to form the corresponding ammonium ylide. The
other issue is the relatively low activation energy for the
competing C−H insertion reaction.[13] The energy barrier for C−H
insertion of metal-nitrenes is often lower than that of N+−N− ylide
far. We developed
a rhodium-catalyzed one-nitrogen insertion
reaction into an amide C−N bond and a sulfonamide S−N bond.
Experimental and theoretical analyses based on density functional
theory indicated that the formal amide insertion proceeds through
the formation of rhodium-associated ammonium ylide between
nitrene and the amide nitrogen followed by an acyl group transfer
concomitant with C−N bond cleavage. The mechanistic studies
rationalized the origin of chemoselectivity between the C−H insertion
and the amide insertion reaction. The present methodology
constitutes the first example of an insertion of nitrene into amide
bonds and provides facile access to unique diazacyclic systems with
N−N bond linkage.
formation,
especially
with
less
nucleophilic
amino
functionality.[12a] As a result, chemoselective formation of N+−N−
ylide with an electronically deactivated amine such as an amide
group over a C−H insertion reaction remains a challenge.[9,14]
Indeed, N+−N− ylide formation from metal-nitrenes and amides
has not yet been reported.[15] These problematic factors have
stagnated the development of new reactions using N+−N− ylide
intermediates, although dipolar nitrogen ylides are potential
intermediates for efficient and unusual transformations.[8a,8c,16,17]
Introduction
The landmark work[ 1 ] by Du Bois in 2001 has inspired
extensive efforts to disclose and apply the unique reactivity of
metal-nitrenes.[2 ] Metal-nitrenes are now well-known to insert
into a C−H bond[ 3 ] and a C=C double bond[ 4 ] to afford the
corresponding C−H aminated products and aziridines via formal
nitrene transfer. [5] These reactivities are widely acknowledged
as powerful tools[ 6 ] for introducing amine functionality into
unactivated chemical bonds, and their mechanisms have been
studied in detail. [7]
The formation of an ammonium ylide, which is initiated by
nucleophilic attack on a nitrogen atom, is an attractive feature in
nitrene chemistry. As evidenced by the limited examples shown
in Scheme 1, however, the current studies are not sufficient. In
2013, Romo et al. succeeded in synthesizing N+−N− ylides[8]
using Rh-nitrene and tertiary alkyl amines for the N−amination of
complex natural products (Scheme 1a).[ 9 ] Pérez et al. also
reported chemoselective N+−N− ylide formations using Ag-
[a]
[b]
M. Kono, Dr. S. Harada, Prof. Dr. T. Nemoto
Scheme 1. N+−N− Ylide Formation of Metal Nitrenes.
Graduate School of Pharmaceutical Sciences, Chiba University
1-8-1, Inohana, Chuo-ku, Chiba 260-8675 (Japan)
E-mail: Sharada@chiba-u.jp, tnemoto@faculty.chiba-u.jp
Prof. Dr. T. Nemoto
Molecular Chirality Research Center, Chiba University
1-33, Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
In our ongoing research aimed at analyzing the reactivity of
nitrene species,[12a] we observed intramolecular N+−N− ylide
formation of Rh-nitrene with an amide nitrogen (Scheme 1c).
Sequential N+→N− acyl transfer of the generated inner salt
spontaneously occurred to cancel the zwitterionic charge.[18] The
observed formal nitrene insertion into an amide C−N bond is an
unexplored reaction in this field. Therefore, it is worth studying
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the details of this amide insertion reaction to expand ylide
chemistry of metal-nitrenes. Herein, we report the development
of the amide insertion reaction of Rh-nitrene, which offers a
unique strategy for amide bond cleavage accompanied by N−C
and N−N bond formation. Mechanistic analysis based on
experimental and computational studies was also performed to
elucidate the reaction pathway.
substituents at the para position of the aromatic ring could be
converted to the corresponding fused diazacycles 2b−2e in
47%−68% yield. Alkyl amides were also applicable in this
reaction to give inserted products 2f and 2g (60% and 52% yield,
respectively). N-Allyl amide containing a terminal alkene moiety
was transformed into 2h in 44% yield. Products 2i[24] and 2j with
cyclopropanes were also obtained without any ring-opened side-
products (73% and 48% yield, respectively). Strained azetidine
2k with N−N bond was synthesized under optimum conditions.
We were next interested in the reaction of amide bioisosteres,
sulfonamides, which are more resistant to acid or base
hydrolysis than the corresponding amides. Fortunately, Rh-
nitrene inserted into a sulfonamide linkage via S−N bond
cleavage, providing 5a−c in moderate yields (40−51%, Table 3),
although additional catalyst (4 mol%) and reagents were
required for complete consumption of the substrate.[25]
Results and Discussion
We first optimized the reaction conditions using L-proline-
derived benzamide 1a bearing a carbamate side-chain as a
nitrene precursor (Table 1). The reaction was examined with
Rh2(NHCOtBu)4, which exhibited the best performance for amide
insertion reactions of Rh-carbene,[19a] in PhCF3 solvent at 80 °C.
The major product, however, was C−H insertion product 3, and
amide insertion product 2a with N−N bond was obtained in only
9% yield (entry 1). The structure of 2a was unambiguously
Table 2. Scope and Limitations of the Amide Insertion Reactions.
20
]
confirmed by X-ray crystallographic analysis.[
Although
21
]
Rh2(espn)2Cl[
produced almost the same results as
Rh2(NHCOtBu)4 (entry 2),[22] the chemoselectivity was reversed
by employing rhodium carboxylate catalyst (2a:3=92:8, 95:5,
[23]
entries 3, 4, respectively). Sterically large Rh2(esp)2
catalyst
further increased both the chemoselectivity and product yield,
affording 2a in 71% yield (2a:3=>97:<3, entry 5). This result
indicates that the C−H insertion process would be more
sensitive to the steric bulk of the rhodium catalyst than the
amide insertion reaction. As no other catalysts, solvents,
oxidants, or additives improved the product yield, we modified
the esp ligands of Rh2(esp)2 by introducing an NO2 or MeO
group to tune the electronic properties of the Rh-nitrene species.
Although the Rh2(esp-NO2)2 catalyst performed worse (entry 6),
Rh2(esp-OMe)2 demonstrated a better result than Rh2(esp)2,
furnishing amide insertion product 2a in 78% yield (entry 7).
[a] brsm = based on recovered starting material.
Table 1. Catalyst and Temperature Effect on Amide Insertion Reaction of Rh-
Nitrene.
Table 3. Insertion Reaction of Rh-nitrene into Sulfonamide Bond.
entry
1
catalyst
yield (%)
ratio
2a
9
3
24
2a : 3
27:73
[a] Reaction was performed at 60 °C.
Rh2(NHCOtBu)4
2
3
4
5
Rh2(espn)2Cl
Rh2(OAc)4
10
33
41
71
25
3
2
29:71
92:8
95:5
To demonstrate the practicality of the formal nitrene insertion
into an amide bond, we performed the reaction utilizing short
peptide 6, affording 7 with α-hydrazino amide unit,[26] which has
been widely applied in medicinal and pharmaceutical chemistry
as a proteasome inhibitor,[27] anti-microbial,[28] and DNA/RNA
interactor[29] (Scheme 2).
Rh2(OCOtBu)4
Rh2(esp)2
n.d.
>97:<3
6
7[a]
Rh2(esp-NO2)2
Rh2(esp-OMe)2
62
78
n.d.
n.d.
>97:<3
>97:<3
(99% ee)
[a] Optically pure 1a (99% ee) was used. n.d. is not detected.
The scope and limitations of the amide insertion reaction are
summarized in Table 2. Benzamides with Me, Cl, MeO, and NO2
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Scheme 2. Conversion from Amide into a Hydrazino Amide in Peptide.
Scheme 3. Plausible Reaction Pathways.
We next explored the reaction mechanism to shed light on
the pathway of the amide insertion reaction. We initially
considered the following three possible routes (Scheme 3). One
is a concerted mechanism in which two new bonds between
nitrene species and an amide group are simultaneously created
(i). Another is the ylide pathway that proceeds via the initial
formation of a Rh-associated N+−N− ylide intermediate resulting
from nucleophilic attack by the amide nitrogen on the Rh-nitrene
followed by N+→N− acyl transfer (ii). The third is a radical
pathway starting from the more stable triplet-spin state of Rh-
nitrene[7b, 30 ] and/or via a minimum energy crossing point
(MECP)[31] (iii).
The radical pathway was initially examined by performing the
reaction with radical trapping agents, but no trapped products
were detected[32] (eq 1,2). Products 2i and 2j with a radical clock
also reject the radical pathway hypothesis because the
33 ]
cyclopropane ring should open[7c
,
if a radical species is
generated as depicted in Scheme 3 (iii).[24,34]
To further elucidate the reaction mechanism, we performed
computational analyses.[ 35 ] Figure 1 shows the calculated
potential energy profiles including the C−H insertion process to
rationalize the origin of the chemoselectivity.[36] As the steric
effects of the used catalysts were critical in the insertion
Figure 1. Reaction Coordinate Diagram and Potential Energy Surface. Optimal geometries and frequencies were computed at the RB3LYP/6-31G* (for H,
C, N, O) and LanL2DZ (Rh) level of theory at 353 K, and single point energies were calculated at the RB97XD/6-311G* (for H, C, N, O) and SDD (Rh) in
chlorobenzene solvent (in kcal/mol, RT is set to zero). H atoms except tert-C−H and N−H are omitted for the sake of clarity. [Rh] is Rh2(esp-OMe)2. Bond
distances and angles from X-ray crystallographic analysis are in parentheses.
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reactions (Table 1), the computations were carried out using
Rh2(esp-OMe)2 and the substrate without structural simplification
at 353 K in PhCl solvent[37] with a closed-shell singlet state[38]
(RB97XD/6-311G* and SDD). Theoretical analyses for the
generation of Rh-nitrene were previously performed,[7a] and we
therefore started our calculations from Rh-nitrene RT. The
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Keywords: amination • heterocycle • insertion • nitrene • ylides
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X-ray data of 2a: CCDC No. 1852134.
K. P. Kornecki, J. F. Berry, Chem. Commun. 2012, 48, 12097.
When using Rh amidate catalysts, the color of the reaction mixture
changed to brilliant red, indicating generation of the Rh2II,III complex.
The Rh2II,III doublet nitrene species reportedly undergoes a nearly
barrierless C−H insertion reaction, and thus the chemoselectivity might
differ between Rh carboxylate and Rh amidate. a) A. Varela-Álvarez, T.
Yang, H. Jennings, K. P. Kornecki, S. N. Macmillan, K. M. Lancaster, J.
B. C. Mack, J. Du Bois, J. F. Berry, D. G. Musaev, J. Am. Chem. Soc.
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When the cis-isomer of 1i was used, a variety of side products were
generated. No ring-opened compounds were detected.
[35]
[36]
[37]
The calculations are performed with Gaussian 16 packages.
Please see the Supporting Information for details.
Similar chemoselectivity was observed between the reaction in PhCF3
and PhCl solvent.[36]
[38]
Calculations with an open-shell triplet pathway were also examined,
but the outcome was not consistent with the present experimental
results and observed chemoselectivity,[36] indicating that the radical
species was not involved. Please see ref 30-31 and the Supporting
Information.
The acyl transfer step occurred via a nonsynchronous concerted
process on the sp2 carbon. S. E. Allen, S.-Y. Hsieh, O. Gutierrez, J. W.
Bode, M. C. Kozlowski, J. Am. Chem. Soc. 2014, 136, 11783 and
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[39]
[23]
[24]
[40]
[41]
Generation of Rh-free ylide from IMcis-C−N was 13.3 kcal/mol
unfavorable.[36]
Carbon-13 kinetic isotope effect was investigated on amide carbonyl
carbon by comparing its integration with those of the other carbons.
The calculated KIE value is 1.005, indicating no kinetic isotope effect.
a) M. Huang, G. E. Garrett, N. Birlirakis, L.Bohé, D. A.Pratt, D. Crich,
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[25]
[26]
X-ray data of 5a: CCDC No. 1852135.
These foldamers display the inimitable hydrazino turn, and the
hydrazidic bond is stable against proteases, G. Lelais, D. Seebach,
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10.1002/chem.201805878
Chemistry - A European Journal
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M. Kono, S. Harada,* T. Nemoto*
Page No. – Page No.
Chemoselective Intramolecular
Formal Insertion Reaction of Rh-
Nitrenes into an Amide Bond over
C−H Insertion
New insertion reaction of metal-nitrene: An intramolecular insertion reaction of
Rh-nitrene into an amide C−N bond and a sulfonamide S−N bond was developed
via an unprecedented N+−N− ylide formation of Rh-nitrene with an amide nitrogen.
Experimental and theoretical analyses on reaction mechanisms were also
conducted, supporting the ylide pathway.
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