Iron-Catalyzed Intramolecular C-H Amination of α-Azidyl Amides

Article abstract of DOI:10.1021/acs.orglett.8b03927

Iron-catalyzed intramolecular C-H amination of aliphatic azides has recently emerged as a powerful tool for the preparation of nitrogen heterocycles. This paper reports that α-azidyl amides can be converted in high efficacy to imidazolinone compounds via intramolecular C(sp³)-H amination by the action of a simple catalytic system composed of FeCl₂ and a β-diketiminate ligand. The reactions provide a simple and atom-economical approach toward polysubstituted imidazolinones.

Full text of DOI:10.1021/acs.orglett.8b03927

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iron-Catalyzed Intramolecular C−H Amination of α‑Azidyl Amides
Xiaopeng Zhao, Siyu Liang, Xing Fan, Tonghao Yang, and Wei Yu*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou, Gansu 730000, P. R. China
S
* Supporting Information
ABSTRACT: Iron-catalyzed intramolecular C−H amination
of aliphatic azides has recently emerged as a powerful tool for
the preparation of nitrogen heterocycles. This paper reports
that α-azidyl amides can be converted in high efficacy to
imidazolinone compounds via intramolecular C(sp3)−H
amination by the action of a simple catalytic system composed
of FeCl2 and a β-diketiminate ligand. The reactions provide a simple and atom-economical approach toward polysubstituted
imidazolinones.
ransition-metal-catalyzed C−H amination reactions
catalyzed intramolecular C(sp3)−H amination of α-azidyl
Tprovide highly effective and atom-economical means for amides following our recent studies on iron-catalyzed acyl
migration of α-azidyl tertiary ketones.13 It was found that by
using a catalytic system of FeCl2 and a β-diketiminate ligand
the insertion of the azidyl nitrogen into the C(sp3)−H bond
attached to the amidyl group took place effectively, affording
polysubstituted imidazolinones in good yields. Herein we
report this result (Scheme 1, (b)).
Imidazolinone is an important heterocyclic motif that
appears in some biologically and pharmaceutically significant
compounds (Figure 1). Commonly used methods to gain
the synthesis of nitrogen-containing compounds.1 Azides are
commonly used nitrogen sources for this purpose because they
are not only readily available but also of minimal environ-
mental impact as only nitrogen gas is released as reaction
waste.2 Previous studies demonstrate that the azide-involved
C−H amination can be enabled by complexes of late first row
transition metals such as iron,3−7 cobalt,8 and copper.9 From a
modern synthetic point of view, using iron as catalyst is
particularly attractive because it is earth-abundant, cheap, and
relatively nontoxic,10 and thus it is highly desirable to apply
iron catalysis to C−H amination reactions. It has been proven
that iron complexes can react with the azidyl group to form
iron-imido or iron-iminyl species,11 which can insert into the
aliphatic C−H bond.12 The importance of this chemistry has
recently been demonstrated by Betley et al., who developed a
highly efficient protocol to convert aliphatic azides to saturated
N-heterocycles via intramolecular C(sp3)−H amination by
using a high-spin iron dipyrrinato complex as catalyst.4 Similar
results were achieved with other iron complexes, as reported by
Lin,5 der Vlugt and de Bruin,6 and Che7 (Scheme 1, (a)).
Inspired by these elegant studies, we explored the iron-
Scheme 1. Iron-Catalyzed Intramolecular C(sp3)−H
Amination of Azides
Figure 1. Representative imidazolinone derivatives.
access to these structure motifs involve reactions of cyanide or
nitrile compounds with ketones, followed by hydrolysis and
oxidative cyclization.14 Although these methods are highly
effective and of general applicability, the use of cyanide or
nitrile precursors, as well as generation of waste over multistep
operations, is a matter of concern from the point of view of
green chemistry. We envisioned that the iron-promoted C−H
Received: December 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03927
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
amination might provide an efficient and atom-economical
approach toward the imidazolinone ring system. In this view,
the conditions developed previously by us for the acyl
migration of α-azidyl tertiary ketones13 were applied to
compound 1a, and the result is illustrated in Table 1.
As shown in Table 1, when N-benzyl α-azidyl amide 1a was
subjected to 1.0 equiv of FeBr2 at elevated temperature in
CH3CN, compound 2a was obtained in moderate yield (Table
1, entry 2). The structure of 2a was confirmed by X-ray
crystallographic analysis (CCDC No. 1872309). However, the
reaction did not take place when the amount of iron salt was
reduced to 0.2 equiv (Table 1, entry 1). A similar result was
obtained when FeCl2 or FeI2 was used as catalyst (Table 1,
entries 3−5). The reaction was greatly facilitated when FeCl2
or FeBr2 was used together with β-diketiminate L1 (entries 6−
11). The conversion was almost quantitative at 100 °C by
using 20 mol % of FeCl2 (or FeBr2) and L1 (entries 6 and 8).
The reaction was less efficient at lower temperatures or with
less amount of catalysts (entries 7, 8, 10, and 11). The effect of
several other ligands (L2−L5) was also tested, but they were
all inferior to L1 (entries 13−16). Besides acetonitrile, several
other solvents, such as THF, dichloroethane, DMSO, and
toluene, were tested for their efficacy, and the result is also
listed in Table 1 (entries 17−20).
Table 1. Screening of Reaction Conditions for the Reaction
The optimized conditions (Table 1, entry 6) were then
applied to a variety of differently substituted α-azidyl amides,
and the result is summarized in Scheme 2. The reaction
proceeded smoothly for a variety of 2-azido-N,N-diarylmethyl-
2-methylpropanamides, with the cyclization products 2b−2i
being formed in high yields. The substituent at the phenyl ring
exhibited a small effect on the reaction but did not influence
much the selectivity (2h). Compounds 2j−2l can also be
prepared with this method, albeit in lower yields. For
compound 1m which bears a benzyl group and a methyl
group at the amidyl nitrogen atom, the reaction afforded two
products (2m-1 and 2m-2) in a ratio of 2:1, with the insertion
at the benzyl position being more favored. When 2-azido-N-
benzyl-2-methyl-N-(1-phenylethyl) propanamide was sub-
jected to the standard conditions, on the other hand, 2n was
generated exclusively in a yield of 89%. This protocol is also
suitable for amination of the unactivated methylene group, as
demonstrated in the case of 2o. However, when 2-azido-2-
methyl-1-(piperidin-1-yl) propan-1-one (1p) and 2-azido-2-
methyl-1-(pyrrolidin-1-yl) propan-1-one (1q) were used as the
substrates, no desired reaction took place. Subsequent
experiments showed that by adding Boc2O into the reaction
vessel 1p and 1q can be converted to the Boc-protected C−H
insertion product 2p′ and 2q′ in yields of 84% and 33%,
respectively (Scheme 3). Variation of substitution pattern at
the α-position was found to have a big influence on the
reaction. As such, while compounds 2r and 2s as well as
monosubstituted 2t and 2u were prepared in good to excellent
yields, we failed to obtain compound 2v by using the same
protocol. It is noteworthy that in most cases illustrated in
Scheme 2 Boc2O was not required to guarantee a complete
conversion and a good yield. Moreover, the reaction can be
realized on gram scales, with no significant loss of efficiency
(see footnote a in Scheme 2; experimental details can be found
in Supporting Information (SI)).
a
of 1a
To further explore the scope of this protocol, the standard
conditions were then applied to compounds 3 and 4, which are
the chosen precursors for the previously reported iron-based
catalytic systems.4−7 Unfortunately, we did not obtain the
desired cyclization products (a complex mixture was
generated). However, by adding Boc2O to the reaction system,
the N-Boc-protected heterocycles 5 and 6 can be obtained in
high yields (Scheme 4).
β-Diketiminates (NacNac) are commonly used ligands
which can coordinate with a variety of metals.15 The studies
by Holland et al. show that iron(I) coordinated with β-
diketiminate can react with an azide to form iron(III)−imido
complexes which are capable of effecting hydrogen atom
transfer16 or nitrene transfer.17 The capacity of NacNac−Fe
complexes for C−H amination was recently explored by Lin et
a
The reactions were conducted on a 0.2 mmol scale in 2 mL of
solvent under an argon atmosphere. The reaction time was 12 h. The
yields are isolated yields. Most of 1a was recovered, with trace of 2a
detected by GC-MS. No reaction took place. Dichloroethane was
used as solvent. THF was used as solvent. DMSO was used as
b
c
d
e
f
g
solvent. Toluene was used as solvent.
B
DOI: 10.1021/acs.orglett.8b03927
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of the Method for the Synthesis of Imidazolinones*
*
a
b
The reactions were conducted on a 0.2 mmol scale. The yields are isolated yields. The reaction was conducted on a 4.0 mmol scale. The ratio
c
d
e
1
was determined by H NMR. The ratio was based on the isolated yields. S. M. decomposed. With most of the reactant recovered.
Scheme 3. Reactions of 1p and 1q in the Presence of Boc2O
dipyrrinato complexes. To shed light on the reaction
mechanism, compound 1w was prepared and subjected to
the standard reaction conditions. It was found that the reaction
gave compound 2w in a yield of 44% (Scheme 5, (a)),
Scheme 5. Mechanistic Studies
Scheme 4. Reactions of 3 and 4
al., who realized the cyclization of aliphatic organic azides by
using a MOF-supported NacNac−Fe(II) complex bound with
a methyl group.5a Compared with the NacNac−Fe complexes
employed by Holland and Lin, the present catalytic system is
readily accessible by mixing FeCl2 and L1 in the reaction vessel
and thus is much simpler to operate when applied to synthesis.
The iron-catalyzed C(sp3)−H amination of azides has been
investigated intensively by Betley’s group by using iron
dipyrrinato complexes as catalyst.4,11 Their studies demon-
strate that the reaction of a high-spin iron(II) dipyrrinato
complex with an azide could form a high-spin ferric iminyl
radical complex, which is highly effective for C(sp3)−H
amination. In the present reactions, the active catalyst is
believed to be an iron(II) complex generated in situ from
FeCl2 and a β-diketiminate ligand. This complex should also be
in a high-spin quintet state (S = 2),18 like the iron(II)
comparable to those of 2j to 2l, with no ring-opening products
being obtained. Subsequent kinetic isotopic experiment with
1j−d as substrate gave a kH/kD value of 4.1 (Scheme 5, (b)),
similar to that reported by Betley’s group.4a Thus, on the basis
of the mechanistic studies by Betley’s group, a possible
mechanism is proposed in Scheme 6 to rationalize the present
reactions: The in situ formed NacNac−Fe(II) complex A first
reacts with the substrate to afford ferric iminyl radical complex
B, which then undergoes intramolecular hydrogen atom
abstraction (HAT) to give intermediate D. The latter is
converted to product 2 via a fast radical recombination. Apart
from this mechanism, it is also possible that the reactions
proceed via intermediacy of ferric-imido intermediate C
through direct C−H insertion (Scheme 6, path (b)). These
C
DOI: 10.1021/acs.orglett.8b03927
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 6. Proposed Mechanism
REFERENCES
■
(1) (a) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417−424.
(b) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011,
40, 5068−5083. (c) Ramirez, T. A.; Zhao, B.; Shi, Y. Chem. Soc. Rev.
2012, 41, 931−942. (d) Jeffrey, J. L.; Sarpong, R. Chem. Sci. 2013, 4,
4092−4106. (e) Louillat, M.-L.; Patureau, F. W. Chem. Soc. Rev. 2014,
43, 901−910. (f) Jiao, J.; Murakami, K.; Itami, K. ACS Catal. 2016, 6,
610−633. (g) Kim, H.; Chang, S. ACS Catal. 2016, 6, 2341−2351.
(h) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017, 117, 9247−9301.
(i) Karimov, R. R.; Hartwig, J. F. Angew. Chem., Int. Ed. 2018, 57, 2−
10.
̈
(2) (a) Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem., Int. Ed. 2005, 44, 5188−5240. (b) Intrieri, D.; Zardi, P.;
Caselli, A.; Gallo, E. Chem. Commun. 2014, 50, 11440−11453.
(c) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040−
1052.
(3) (a) Shen, M.; Driver, T. G. Org. Lett. 2008, 10, 3367−3370.
(b) Stokes, B. J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G.
Org. Lett. 2010, 12, 2884−2887. (c) Nguyen, Q.; Nguyen, T.; Driver,
T. G. J. Am. Chem. Soc. 2013, 135, 620−623. (d) Liu, Y.; Wei, J.; Che,
C.-M. Chem. Commun. 2010, 46, 6926−6928. (e) Bonnamour, J.;
Bolm, C. Org. Lett. 2011, 13, 2012−2014. (f) Alt, I. T.; Plietker, B.
Angew. Chem., Int. Ed. 2016, 55, 1519−1522. (g) Alt, I. T.; Guttroff,
C.; Plietker, B. Angew. Chem., Int. Ed. 2017, 56, 10582−10586.
(4) (a) Hennessy, E. T.; Betley, T. A. Science 2013, 340, 591−595.
(b) Iovan, D. A.; Wilding, M. J.; Baek, Y.; Hennessy, E. T.; Betley, T.
A. Angew. Chem., Int. Ed. 2017, 56, 15599−15602.
(5) (a) Thacker, N. C.; Lin, Z.; Zhang, T.; Gilhula, J. C.; Abney, C.
W.; Lin, W. J. Am. Chem. Soc. 2016, 138, 3501−3509. (b) Thacker, N.
C.; Ji, P.; Lin, Z.; Urban, A.; Lin, W. Faraday Discuss. 2017, 201, 303−
315.
(6) Bagh, B.; Broere, D. L. J.; Sinha, V.; Kuijpers, P. F.; van Leest, N.
P.; de Bruin, B.; Demeshko, S.; Siegler, M. A.; van der Vlugt, J. I. J.
Am. Chem. Soc. 2017, 139, 5117−5124.
(7) Shing, K.-P.; Liu, Y.; Cao, B.; Chang, X.-Y.; You, T.; Che, C.-M.
Angew. Chem., Int. Ed. 2018, 57, 11947−11951.
(8) (a) Ruppel, J. V.; Kamble, R. M.; Zhang, X. P. Org. Lett. 2007, 9,
4889−4892. (b) Lu, H.; Subbarayan, V.; Tao, J.; Zhang, X. P.
Organometallics 2010, 29, 389−393. (c) Lyaskovskyy, V.; Suarez, A. I.
O.; Lu, H.; Jiang, H.; Zhang, X. P.; de Bruin, B. J. Am. Chem. Soc.
2011, 133, 12264−12273. (d) Villanueva, O.; Weldy, N. M.; Blakey,
S. B.; MacBeth, C. E. Chem. Sci. 2015, 6, 6672−6675. (e) Tseberlidis,
G.; Zardi, P.; Caselli, A.; Cancogni, D.; Fusari, M.; Lay, L.; Gallo, E.
Organometallics 2015, 34, 3774−3781. (f) Kuijpers, P. F.; Tiekink, M.
J.; Breukelaar, W. B.; Broere, D. J.; van Leest, N. P.; van der Vlugt, J.
I.; Reek, J. N. H.; de Bruin, B. Chem. - Eur. J. 2017, 23, 7945−7952.
(g) Goswami, M.; Geuijen, P.; Reek, J. N. H.; de Bruin, B. Eur. J.
Inorg. Chem. 2018, 2018, 617−626.
two mechanisms cannot be distinguished at this stage as no
intermediates could be isolated and characterized.
In summary, we have developed a simple effective protocol
for the intramolecular C−H amination of organic azides. This
protocol features the use of cheap, readily available FeCl2 and
β-diketiminate as catalyst and is highly effective for the
denitrogenative cyclization of α-azidyl amides. In this way,
polysubstituted imidazolinones can be prepared efficiently in
an atom-economical way. We hope that the present method
might find applications in the synthesis of medicinally
important compounds. Further work is being done in this
laboratory to search for more efficient iron-based catalytic
systems for the azide-involved C−H amination reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03927.
General experimental procedures, characterization data
1
for the substrates and products, and copies of H NMR
and 13C NMR spectra (PDF)
Accession Codes
CCDC 1872309 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(9) (a) Badiei, Y. M.; Dinescu, A.; Dai, X.; Palomino, R. M.;
Heinemann, F. W.; Cundari, T. R.; Warren, T. H. Angew. Chem., Int.
Ed. 2008, 47, 9961−9964. (b) Aguila, M. J. B.; Badiei, Y. M.; Warren,
T. H. J. Am. Chem. Soc. 2013, 135, 9399−9406. (c) Fauche, K.;
Nauton, L.; Jouffret, L.; Cisnetti, F.; Gautier, A. Chem. Commun.
2017, 53, 2402−2405.
(10) Furstner, A. ACS Cent. Sci. 2016, 2, 778−789.
̈
AUTHOR INFORMATION
■
(11) (a) King, E. R.; Hennessy, E. T.; Betley, T. A. J. Am. Chem. Soc.
2011, 133, 4917−4923. (b) Iovan, D. A.; Betley, T. A. J. Am. Chem.
Soc. 2016, 138, 1983−1993. (c) Wilding, M. J. T.; Iovan, D. A.;
Betley, T. A. J. Am. Chem. Soc. 2017, 139, 12043−12049. (d) Wilding,
M. J. T.; Iovan, D. A.; Wrobel, A. T.; Lukens, J. T.; MacMillan, S. N.;
Lancaster, K. M.; Betley, T. A. J. Am. Chem. Soc. 2017, 139, 14757−
14766.
Corresponding Author
*E-mail: yuwei@lzu.edu.cn.
ORCID
Wei Yu: 0000-0002-3131-3080
Notes
(12) For examples of iron-catalyzed C(sp3)−H amination with
iminoiodinane precursors, see: (a) Paradine, S. M.; White, M. C. J.
Am. Chem. Soc. 2012, 134, 2036−2039. (b) Liu, Y.; Guan, X.; Wong,
E.; Liu, P.; Huang, J.-S.; Che, C.-M. J. Am. Chem. Soc. 2013, 135,
7194−7204. (c) Liu, Y.; Chen, G.-Q.; Tse, C.-W.; Guan, X.; Xu, Z.-J.;
Huang, J.-S.; Che, C.-M. Chem. - Asian J. 2015, 10, 100−105.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the National Natural Science Foundation of
China (Nos. 21772077 and 21372108) for financial support.
■
D
DOI: 10.1021/acs.orglett.8b03927
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(13) Yang, T.; Fan, X.; Zhao, X.; Yu, W. Org. Lett. 2018, 20, 1875−
1879.
(14) (a) Botteghi, C.; Marchetti, M.; Paganelli, S.; Persi-Paoli, F.
Tetrahedron 2001, 57, 1631−1637. (b) Zhang, Y.; Zhang, Y.; Zhang,
R. CN Patent, 108218841, Mar 6, 2018. (c) Dattatr, S. S.; Mahadev,
N. A.; Arvind, K. G.; Girish, K. S.; Parshuram, P. M. IN Patent,
2011MU01548, Dec 7, 2012. (d) Lin, Z.; Jason, P.; Cornelius, O.; Ian,
H. WO Patent, 2010135350, Nov 25, 2010.
(15) (a) Bourget-Merle, L.; Lappert, M. F.; Severn, J. R. Chem. Rev.
2002, 102, 3031−3065. (b) Tsai, C. Coord. Chem. Rev. 2012, 256,
722−758. (c) Chen, S. M.; Bellows, C.; Holland, P. L. Dalton Trans
2015, 44, 16654−16670.
(16) (a) Eckert, N. A.; Vaddadi, S.; Stoian, S.; Lachicotte, R. J.;
Cundari, T. R.; Holland, P. L. Angew. Chem., Int. Ed. 2006, 45, 6868−
6871. (b) Cowley, R. E.; Eckert, N. A.; Vaddadi, S.; Figg, T. M.;
Cundari, T. R.; Holland, P. L. J. Am. Chem. Soc. 2011, 133, 9796−
9811. (c) Cowley, R. E.; Holland, P. L. Inorg. Chem. 2012, 51, 8352−
8361.
(17) (a) Cowley, R. E.; Elhaik, J.; Eckert, N. A.; Brennessel, W. W.;
Bill, E.; Holland, P. L. J. Am. Chem. Soc. 2008, 130, 6074−6075.
(b) Cowley, R. E.; Eckert, N. A.; Elhaik, J.; Holland, P. L. Chem.
Commun. 2009, 1760−1762.
(18) Holland, P. L. Acc. Chem. Res. 2008, 41, 905−914.
E
DOI: 10.1021/acs.orglett.8b03927
Org. Lett. XXXX, XXX, XXX−XXX