Synthetic Utility of N-Benzoyloxyamides as an Alternative Precursor of Acylnitrenoids for γ-Lactam Formation

Article abstract of DOI:10.1021/acs.orglett.9b00791

Described herein is the development of a new entry of acylnitrenoid precursors for γ-lactam synthesis via an intramolecular C-H amidation reaction. Upon Ir catalysis, N-benzoyloxyamides serve as efficient substrates to afford 5-membered amides. Mechanistic studies revealed that the generation of a putative Ir-carbonylnitrenoid via N-O bond cleavage is facilitated by the chelation of countercations. This protocol offers a convenient and step-economic route to γ-lactams starting from the corresponding carboxylic acids.

Full text of DOI:10.1021/acs.orglett.9b00791

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthetic Utility of N‑Benzoyloxyamides as an Alternative Precursor
of Acylnitrenoids for γ‑Lactam Formation
†
,‡,§
†,‡,§
,†,‡
Soohee Huh,
Seung Youn Hong,
and Sukbok Chang*
†
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
Center for Catalytic Hydrocarbon Functionalization, Institute for Basic Science (IBS), Daejeon 34141, Korea
‡
*
S Supporting Information
ABSTRACT: Described herein is the development of a new
entry of acylnitrenoid precursors for γ-lactam synthesis via an
intramolecular C−H amidation reaction. Upon Ir catalysis, N-
benzoyloxyamides serve as efficient substrates to afford 5-
membered amides. Mechanistic studies revealed that the
generation of a putative Ir−carbonylnitrenoid via N−O bond
cleavage is facilitated by the chelation of countercations. This protocol offers a convenient and step-economic route to γ-lactams
starting from the corresponding carboxylic acids.
yclic amides are ubiquitous in alkaloid natural products
and biologically active compounds. In particular, γ-
Schoenebeck and Rovis reported the transformation of primary
amines to lactams via α-alkylation.
On the other hand, a group-transfer approach based on the
1
4
C
lactams are a privileged scaffold that is widely present in
2
important pharmaceutical agents (Scheme 1a). Therefore, the
metal−acylnitrenoid intermediacy is also appealing in the
5
development of efficient and selective synthetic routes to this
construction of cyclic amides. However, this method has been
5
-membered amide starting from readily available compounds
challenging mainly due to the difficulty in controlling the
reactivity of the putative carbonylnitrene intermediates since
they are prone to decompose to isocyanates via a Curtius-type
is of great interest. For example, Gaunt et al. developed a C−H
carbonylative cyclization of secondary aliphatic amines using
carbon monoxide to give functionalized lactams. In addition,
3
6
rearrangement. Recently, we showed that (pentamethyl)-
cyclopentadienyl (Cp*)-based Ir complexes with engineered
bidentate ligands display an unprecedented performance in
catalytic C−H amidation of dioxazolones with effective
Scheme 1. γ-Lactams via C−H Amidation
7
suppression of such a side pathway (Scheme 1b, top). The
high reactivity was attributed to the modulated Lewis acidity of
the Ir metal center in the tailored catalysts, thereby facilitating
an oxidative coupling of dioxazolone substrates to generate the
key Ir−nitrenoids. This approach allows a facile access to a
broad range of γ-lactams starting from readily available
7c
carboxylic acids even in an asymmetric manner.
As part of our research program toward the development of
8
selective and efficient C−H amidation reactions, we
wondered whether an alternative type of nitrene precursors
in lieu of oxazolones could be applied in our Cp*Ir catalyst
systems. Herein, we present a synthetic utility of N-
benzoyloxyamides as an efficient substrate for the γ-lactam
synthesis via a C−H insertion pathway (Scheme 1b, bottom).
Importantly, N-benzoyloxyamide derivatives display com-
parable reactivity with dioxazolones as a carbonylnitrenoid
precursor under the employed Ir catalyst system. Moreover, N-
benzoyloxyamides can be readily prepared from the corre-
sponding carboxylic acids, and they are easy to handle and
stable to storage. Experimental and theoretical studies revealed
that the observed reactivity of N-benzoyloxyamides is
Received: March 4, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00791
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
leveraged by the facile generation of key Ir−carbonylnitrenoid
intermediate, where countercations of base additives were
found to critically affect this process.
At the outset of the present study, we sought the optimal
carbonylnitrene precursors for γ-lactam synthesis with iridium
catalysis (Table 1). Iridium complex A was chosen as a model
iridium catalytic conditions in hexafluoro-2-propanol (HFIP)
solvent in the presence of a stoichiometric amount of K CO
2
3
additive (entry 5).
A greater improvement was achieved when N-{3,5-bis-
(trifluoromethyl)benzoyl}oxyamide (6) was applied (entry 6).
Finally, a quantitative product yield was attained in 2,2,2-
trifluorethanol (TFE) solvent at 60 °C (entry 7). However, the
choice of solvent was found to be influential on the reaction
efficiency as demonstrated in entries 6−11. A similar level of
cyclization was observed even at slightly lower temperature in
TFE (40 °C, entry 12). However, the amount of K CO
a
Table 1. Optimization of Reaction Parameters
2
3
additive affected the reaction progress significantly (compare
entries 12 and 13), and only low product yield was obtained in
the absence of K CO (entry 14).
2
3
Having observed the promising reactivity on the lactamiza-
tion, we attempted to preliminarily rationalize the working
mode of N-benzoyloxyamides as an efficient carbonylnitrenoid
7a
precursor under the employed Ir catalyst system (Scheme 2).
Scheme 2. Effects of Countercations of Carbonates
c
entry
sub
T (°C)
solvent
7 (%)
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
6
6
6
6
6
6
6
6
60
60
60
60
60
60
60
60
60
60
60
40
40
40
(CF ) CHOH (HFIP)
HFIP
HFIP
HFIP
HFIP
HFIP
NR
18
17
30
59
85
>95
87
70
48
3
2
CF CH OH (TFE)
3
2
As seen in Table 1 (entries 12−14), the effect of K CO
2
3
CH OH
3
additive was especially noteworthy in the lactam formation. In
fact, Lebel and co-workers described that countercations of
carbonates are involved in the generation of putative Rh−
nitrene species in the C−H amination of N-sulfonyloxycarba-
CH Cl (DCM)
2
2
1
1
1
1
1
0
1
2
3
4
Cl CHCHCl (TCE)
2
2
CH CN
60
>95
59
3
TFE
TFE
TFE
12
d
mates. We first performed a series of catalytic reactions in the
presence of analogous base additives (Scheme 2). While
lithium carbonate and cesium carbonate were less effective,
Na CO was almost as effective as K CO in the cyclization of
e
31
a
F
Reaction conditions: substrate (0.05 mmol), A (5 mol %), NaBAr
4
b
2
3
2
3
(
5 mol %), and K CO (1.0 equiv) in the indicated solvent. ORTEP
2 3
c
1
6. On the other hand, the additive effect of K CO was
diagrams of 6. Disorder of fluorine atoms was omitted for clarity.
H
2 3
d
e
significantly decreased when the reaction was carried out in the
presence of 2 equiv of 18-crown-6. This result led us to assume
that the countercations of carbonate additives would be
involved presumably in the nitrenoid-generating stage.
For a better understanding of the role of countercations in
the reaction progress, their working mode was evaluated with
density functional theory (DFT) calculations on the basis of
plausible intermediates (Figure 1). We chose the potassium
system as a representative model to rationalize the proposed
cation assistance. Recently, the group of Lebel showed that a
countercation is embedded in the presumed carbamate-
NMR yield. 20 mol % of K CO . Without K CO .
2
3
2
3
catalyst since it was proven to be highly effective when
7
a
dioxazolones were employed in our recent report. As an
acylnitrenoid precursor, hydroxamic acid derivatives were first
envisaged to be examined since they can be readily prepared
from the corresponding carboxylic acids. In fact, a few
research groups employed the related compounds as nitrogen
9
sources in the intermolecular C−H amidation reactions under
10
various conditions. In addition, the Rovis group demon-
strated that N-pivalyloxyamides were utilized as acylnitrene
precursors in the catalytic diamidation reaction of terminal
2
12d
2
coordinated Rh species via a κ -bidentate chelating mode.
On the basis of this literature, complexes I-1 (7-membered-κ -
1
1
2
olefins. When a substrate bearing N-methoxyamide (1) was
subjected to iridium catalysis using A (5 mol %), no desired
lactam product (7) was obtained (entry 1). In contrast,
reactions of N-acyloxy variants (2, 3, or 4) showed promising
reactivities (entries 2−4), suggesting that the nature of N-
substituents is critical for the cyclization reactivity. Indeed, a
notable product yield (59%) was obtained when N-
O,O′-chelate; marked with blue), I-2 (5M-κ -N,O; black), and
2
I-3 (5M-κ -O′,O″; red) were considered (Figure 1a). In the
subsequent formation of the putative Ir−carbonylnitrenoid
intermediate II, the individual complex was calculated to
traverse I-TS-1, I-TS-2, and I-TS-3, respectively, via a
1
3
potassium-assisted N−O bond cleavage. The activation
barrier was estimated to be 15.6 kcal/mol for I-1 (via I-TS-
1), whereas higher energy was calculated for the other
(
pentafluorobenzoyl)oxyamide (5) was subjected to the
B
DOI: 10.1021/acs.orglett.9b00791
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope
Figure 1. (a) Three plausible binding modes of a countercation. (b)
Energy profiles for the proposed pathways at the PCM(TFE)-M06/
SDD+6-311++G**//B3LYP/Lanl2dz+6-31G** level.
proposed complexes: 22.3 kcal/mol for I-2 (via I-TS-2) and
a
Reaction conditions: substrate (0.2 mmol), A (5 mol %), NaBArF
4
2
2.5 kcal/mol for I-3 (via I-TS-3).
Most importantly, this process of forming the Ir−carbon-
(
5 mol %), and K CO (1.0 equiv) in TFE (2.4 mL) at 40 °C for 12
2
3
b
F
h. A (10 mol %) and NaBAr (10 mol %) were used.
4
ylnitrenoid intermediate II was calculated to become energeti-
cally more demanding without potassium assistance in which
the barrier was calculated to be 21.3 kcal/mol in the absence of
potassium ion (see the SI for details). This result demonstrates
that the existence of countercations exerts a beneficial effect, in
particular on the generation of Ir−nitrenoid. The reaction
efficiency was dependent on each countercation of base
additives, although the exact reason is not clear at the present
stage. Finally, C−H insertion of the resultant intermediate II
will occur in a concerted and asynchronous manner with a
barrier of only 10.9 kcal/mol to furnish the desired product III.
The general applicability of the present amidation of N-{3,5-
bis(trifluoromethyl)benzoyl}oxyamides was next explored
addition, a tricyclic lactam 16 was readily synthesized with high
selectivity and efficiency.
Generation of a quaternary carbon center in a lactam
scaffold was enabled efficiently via the amidation of tertiary C−
H bonds (17 and 18). Significantly, aliphatic secondary C−H
bonds of N-benzoyloxyamide substrates bearing n-butyl,
cyclopentyl, cyclohexyl, and adamantyl groups were success-
fully amidated to give the corresponding lactams 19, 20, 21,
and 22, respectively. In addition, a γ-lactam product bearing a
propargylic substituent could be obtained albeit in moderate
14
yield (23).
(
Scheme 3). Substrates bearing benzylic γ-C−H bonds
A practical aspect of the present protocol was briefly
examined (Scheme 4). Representatively, a substrate 6 was
demonstrated to be prepared in a step-economical fashion
from 4-phenylbutyric acid (24, 73% yield). It should be noted
that most substrates examined in this study are bench-stable
crystalline solid (for a few months), and they can be readily
isolated by recrystallization. When the reaction was conducted
on a larger scale, product 7 was isolated in 82% yield with
recovery of 3,5-bis(trifluoromethyl)benzoic acid in 69% yield
(Scheme 4a). Lastly, the current procedure of γ-lactam
formation starting from N-benzoyloxyamides was briefly
compared with our previous dioxazolone procedure (Scheme
4b). Starting from phthalimide-protected L-β-leucine 25, the
smoothly underwent the desired amidation to afford 5-aryl-2-
pyrrolidinones in excellent yields (7−11). Heterocycles such as
benzothiozole and benzoxazole were well tolerated under the
optimal reaction conditions (12 and 13, respectively). The
position of a substituent in the alkyl linker was found to affect
the diastereoselectivity in substituted γ-lactam products. For
instance, when a methyl group is present at the α-position
relative to the amide, a mixture of anti- and syn-isomers was
obtained in a 1.7:1 ratio (14/14′) in moderate combined
yields. In contrast, the C−N bond formation occurred almost
exclusively in an anti-selective manner with higher yield when a
methyl group is positioned at β- to the amide moiety (15). In
C
DOI: 10.1021/acs.orglett.9b00791
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Practical Aspect of Present Protocol
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: sbchang@kaist.ac.kr.
ORCID
Sukbok Chang: 0000-0001-9069-0946
Author Contributions
§S.H. and S.Y.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Institute of Basic Science.
Single-crystal X-ray diffraction experiments with synchrotron
radiation were performed at the MicroMX 11C beamline in the
Pohang Accelerator Laboratory.
REFERENCES
■
(
1) (a) Sammes, P. G. Chem. Rev. 1976, 76, 113. (b) Caruano, J.;
Muccioli, G. G.; Robiette, R. Org. Biomol. Chem. 2016, 14, 10134.
(2) (a) Fenteany, G.; Standaert, R.; Lane, W.; Choi, S.; Corey, E.;
Schreiber, S. Science 1995, 268, 726. (b) Hayashi, Y.; Shoji, M.;
Yamaguchi, J.; Sato, K.; Yamaguchi, S.; Mukaiyama, T.; Sakai, K.;
Asami, Y.; Kakeya, H.; Osada, H. J. Am. Chem. Soc. 2002, 124, 12078.
(
1
c) Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004,
26, 6230. (d) Jang, J.-H.; Asami, Y.; Jang, J.-P.; Kim, S.-O.; Moon, D.
O.; Shin, K.-S.; Hashizume, D.; Muroi, M.; Saito, T.; Oh, H.; Kim, B.
Y.; Osada, H.; Ahn, J. S. J. Am. Chem. Soc. 2011, 133, 6865. (e) Deng,
J.; Zhu, B.; Lu, Z.; Yu, H.; Li, A. J. Am. Chem. Soc. 2012, 134, 920.
(
f) Lee, K. L.; Ambler, C. M.; Anderson, D. R.; Boscoe, B. P.; Bree, A.
G.; Brodfuehrer, J. I.; Chang, J. S.; Choi, C.; Chung, S.; Curran, K. J.;
Day, J. E.; Dehnhardt, C. M.; Dower, K.; Drozda, S. E.; Frisbie, R. K.;
Gavrin, L. K.; Goldberg, J. A.; Han, S.; Hegen, M.; Hepworth, D.;
Hope, H. R.; Kamtekar, S.; Kilty, I. C.; Lee, A.; Lin, L.-L.; Lovering, F.
E.; Lowe, M. D.; Mathias, J. P.; Morgan, H. M.; Murphy, E. A.;
Papaioannou, N.; Patny, A.; Pierce, B. S.; Rao, V. R.; Saiah, E.;
Samardjiev, I. J.; Samas, B. M.; Shen, M. W. H.; Shin, J. H.; Soutter,
H. H.; Strohbach, J. W.; Symanowicz, P. T.; Thomason, J. R.;
Trzupek, J. D.; Vargas, R.; Vincent, F.; Yan, J.; Zapf, C. W.; Wright, S.
W. J. Med. Chem. 2017, 60, 5521.
synthesis of a lactam 28 (99% ee) was achieved in three steps
7a
(
15% overall yields) through the dioxazolone route. On the
other hand, the present protocol was found to be more
efficient to produce the same product 28 also with no erosion
of enantiomeric excess.
In summary, we have successfully utilized a new type of
nitrenoid precursor, N-benzoyloxyamide derivatives, toward
the Ir-catalyzed intramolecular C−H amidation reaction.
Mechanistic studies revealed that the putative Ir−carbon-
ylnitrene intermediate forms more readily in the presence of
carbonate additives presumably by the countercation-assisted
N−O bond cleavage. The present protocol of using N-{3,5-
bis(trifluoromethyl)benzoyloxy}amides was found to be a
convenient alternative to the previous dioxazolone procedure
toward the γ-lactam formation from carboxylic acids.
(
3) Png, Z. M.; Cabrera-Pardo, J. R.; Peiro
Chem. Sci. 2018, 9, 7628.
4) Ye, J.; Kalvet, I.; Schoenebeck, F.; Rovis, T. Nat. Chem. 2018, 10,
037.
5) For selected reviews, see: (a) Davies, H. M. L.; Manning, J. R.
́
Cadahía, J.; Gaunt, M. J.
(
1
(
Nature 2008, 451, 417. (b) Dequirez, G.; Pons, V.; Dauban, P. Angew.
Chem., Int. Ed. 2012, 51, 7384. (c) Roizen, J. L.; Harvey, M. E.; Du
Bois, J. Acc. Chem. Res. 2012, 45, 911. (d) Jeffrey, J. L.; Sarpong, R.
Chem. Sci. 2013, 4, 4092. (e) Jiao, J.; Murakami, K.; Itami, K. ACS
Catal. 2016, 6, 610. (f) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017,
ASSOCIATED CONTENT
Supporting Information
■
*
S
117, 9247.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00791.
(
6) (a) Lebel, H.; Leogane, O. Org. Lett. 2005, 7, 4107. (b) Li, D.;
Wu, T.; Liang, K.; Xia, C. Org. Lett. 2016, 18, 2228.
(7) (a) Hong, S. Y.; Park, Y.; Hwang, Y.; Kim, Y. B.; Baik, M.-H.;
Chang, S. Science 2018, 359, 1016. (b) Hwang, Y.; Park, Y.; Kim, Y.
B.; Kim, D.; Chang, S. Angew. Chem., Int. Ed. 2018, 57, 13565.
c) Park, Y.; Chang, S. Nat. Catal. 2019, 2, 219.
8) (a) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.;
Cartesian coordinates and structures for the optimized
structures and transition states; additional crystallo-
graphic and NMR data (PDF)
(
(
Accession Codes
Chang, S. J. Am. Chem. Soc. 2012, 134, 9110. (b) Ryu, J.; Kwak, J.;
Shin, K.; Lee, D.; Chang, S. J. Am. Chem. Soc. 2013, 135, 12861.
CCDC 1900860−1900861 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(
c) Park, Y.; Park, K. T.; Kim, J. G.; Chang, S. J. Am. Chem. Soc. 2015,
1
1
1
37, 4534. (d) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48,
040. (e) Hwang, Y.; Park, Y.; Chang, S. Chem. - Eur. J. 2017, 23,
1147.
(9) For a recent enzymatic asymmetric C−H amidation of N-
pivaloyloxyamides, see: Cho, I.; Jia, Z.-J.; Arnold, F. H. ChemRxiv
D
DOI: 10.1021/acs.orglett.9b00791
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
019, http://doi.org/10.26434/chemrxiv-7711418.v1 (posted Feb
1
4, 2019).
10) (a) Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2013, 15,
Chem. 2014, 12, 6831. (c) Zhou, B.; Du, J.; Yang, Y.; Feng, H.; Li, Y.
Org. Lett. 2014, 16, 592. (d) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. J.
Am. Chem. Soc. 2010, 132, 12862. (e) John, A.; Byun, J.; Nicholas, K.
M. Chem. Commun. 2013, 49, 10965.
(
(
11) Conway, J. H.; Rovis, T. J. Am. Chem. Soc. 2018, 140, 135.
12) (a) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005,
1
27, 14198. (b) Lebel, H.; Huard, K. Org. Lett. 2007, 9, 639.
(
c) Lebel, H.; Mamani Laparra, L.; Khalifa, M.; Trudel, C.; Audubert,
C.; Szponarski, M.; Dicaire Leduc, C.; Azek, E.; Ernzerhof, M. Org.
Biomol. Chem. 2017, 15, 4144. (d) Azek, E.; Khalifa, M.;
Bartholomeu
́
̈
s, J.; Ernzerhof, M.; Lebel, H. Chem. Sci. 2019, 10, 718.
(
13) For selected examples of external oxidant-free transformations
initiated via a N−O bond cleavage, see: (a) Munnuri, S.; Adebesin, A.
M.; Paudyal, M. P.; Yousufuddin, M.; Dalipe, A.; Falck, J. R. J. Am.
Chem. Soc. 2017, 139, 18288. (b) Prasanthi, A. V. G.; Begum, S.;
Srivastava, H. K.; Tiwari, S. K.; Singh, R. ACS Catal. 2018, 8, 8369.
(
1
c) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2011,
33, 6449. (d) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J.
Am. Chem. Soc. 2011, 133, 2350. (e) Hong, S. Y.; Jeong, J.; Chang, S.
Angew. Chem., Int. Ed. 2017, 56, 2408.
(
14) Hong, S. Y.; Son, J.; Kim, D.; Chang, S. J. Am. Chem. Soc. 2018,
1
40, 12359.
E
DOI: 10.1021/acs.orglett.9b00791
Org. Lett. XXXX, XXX, XXX−XXX