Iron-Phosphine Complex-Catalyzed Intramolecular C(sp3)-H Amination of Azides

Article abstract of DOI:10.1021/acs.orglett.0c00308

Fe(II)-phosphine complex [Fe(dpbz)]Cl₂ was demonstrated to be effective for the intramolecular C(sp³)-H amination of organic azides. This catalyst exhibited a high catalytic capacity for the transformations from α-azido amides to imi

Full text of DOI:10.1021/acs.orglett.0c00308

pubs.acs.org/OrgLett
Letter
Iron−Phosphine Complex-Catalyzed Intramolecular C(sp3)−H
Amination of Azides
Siyu Liang, Xiaopeng Zhao, Tonghao Yang, and Wei Yu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00308
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Fe(II)−phosphine complex [Fe(dpbz)]Cl2 was
demonstrated to be effective for the intramolecular C(sp3)−H
amination of organic azides. This catalyst exhibited a high catalytic
capacity for the transformations from α-azido amides to
imidazolinones. Cyclization of simple aliphatic azides can be
realized as well by using [Fe(dpbz)]Cl2 as the catalyst.
Scheme 1. Iron-Catalyzed Intramolecular C(sp3)−H
Amination of Aliphatic Azides
atalytic C−H amination mediated by metal−nitrene
Cintermediates is of great interest to chemists because of
its potential usefulness in the synthesis of nitrogen-containing
compounds.1 These transformations provide a powerful
means for the preparation of N-heterocycles in an atom-
economical and step-economical way.2 Although noble
transition metals such as rhodium and ruthenium can readily
react with iminoiodinanes or azides to form nitrenoids of
high C−H insertion capacity,3,4 increasing attention has
recently been paid to the reactions promoted by late first-row
transition metals such as iron5 and cobalt.6 These first-row
metals are cheap, earth-abundant, and less toxic and therefore
are highly preferable as catalysts in practical synthesis.
Organic azides are very useful compounds in organic
synthesis.7 They are viewed as attractive nitrogen sources for
C−H amination because of their ready availability as well as
their high reactivity.8 Moreover, using azides as the
precursors of nitrenoids is highly desirable in terms of
atom economy because only nitrogen gas is released as the
byproduct. Recent studies by Betley show that high-spin iron
complexes can form iron−imido or iron−iminyl species with
organic azides, and these reactive species are capable of
aliphatic C−H insertion.9 By using high-spin iron−
dipyrrinato complexes as a catalyst, Betley developed a new
atom-economical strategy for the synthesis of pyrrolidines
from aliphatic azides via intramolecular C(sp3)−H amina-
tion.10 The same transformations were also achieved by using
other nitrogen-bound iron complexes, as reported by Lin,11
van der Vlugt and de Bruin,12 and Che13 (Scheme 1a).
During our investigation of the iron-catalyzed amination
reactions of organic azides,14 we found that the intra-
molecular C(sp3)−H amination can be enabled by using a
simple catalytic system composed of FeCl2 and a β-
diketiminate ligand,15 and thus we developed a new efficient
method for the synthesis of structurally useful imidazolinone
compounds from α-azido amides (Scheme 1b).16 Although
this catalytic system has the merit of simplicity, a high
reaction temperature is required to guarantee complete
conversion and a high yield. This problem drove us to
search for more effective iron catalysts. So far, the reported
iron catalysts used for the C(sp3)−H amination of aliphatic
azides are mostly limited to the nitrogen-ligand-bound
complexes,5,17 and to our knowledge, there has not been a
Received: January 22, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00308
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
report on using iron−phosphine complexes for this purpose.
Our recent investigation shows that the high-spin 1,2-
bis(diphenylphosphino)benzene (dpbz) Fe(II) complex [Fe-
(dpbz)]Br2 ((dpbz = 1,2-bis(diphenylphosphino)benzene))
can catalyze the 1,2-acyl migration of tertiary α-azido
ketones.18 We hoped that the same type of catalyst could
also be applicable to the conversion of α-azido amides to
imidazolinones. Indeed, it was found that the complex
[Fe(dpbz)]Cl2 exhibited high catalytic capacity for the
intramolecular C(sp3)−H amination of α-azido amides. It is
superior to the previous catalytic system of FeCl2/β-
diketiminate ligand in that the reaction can be realized at a
lower temperature with a lower amount of catalyst. Moreover,
simple aliphatic azides can also undergo C(sp3)−H amination
by catalysis of [Fe(dpbz)]Cl2 in the presence of di-tert-butyl
dicarbonate ((Boc)2O). Herein we report our result.
In the initial stage of this investigation, three known high-
spin 1,2-bis(diphenylphosphino)benzene Fe(II) complexes
(Cat-1, Cat-2, and Cat-3),19 which were applied in our
previous study of the 1,2-acyl migration of tertiary α-azido
ketones,18 were chosen as the catalyst to effect the reaction of
2-azido-N,N-dibenzyl-2-methylpropanamide (1a). The result
is summarized in Table 1. It can be seen that all of these
catalysts can prompt the anticipated transformation in
dichloromethane (DCM) at a moderate temperature of 40
°C, among which [Fe(dpbz)]Cl2 (Cat-1) exhibited the
highest efficiency. As such, by using 5 mol % of Cat-1 as
the catalyst, compound 2a was generated in a yield of 99%
after 24 h. The reaction also proceeded in chloroform, 1,2-
dichloroethane (DCE), 1,2-dibromoethane (DBE), toluene,
and acetonitrile, but the yields of 2a were considerably lower
in these solvents. By contrast, the reaction did not take place
in chlorobenzene or dimethylformamide (DMF).
The optimal conditions (Table 1, entry 2) were then
applied to variously substituted α-azido amides, and the result
is depicted in Scheme 2. The protocol worked well for N,N-
dibenzyl tertiary α-azido amides, with the corresponding
imidazolinone products being generated in good to excellent
yield. Notably, the reaction can be performed on gram scale
without much loss in efficacy (Scheme 2, foonote a).
Halogen atoms at the phenyl ring have no effect on the
reaction, but the yield is influenced to some extent by the
position of the methoxy group.15 When compound 1h was
used as the substrate, the reaction afforded 2h-1 and 2h-2 in
a ratio of 1:1. Compounds 1i−l, which bear a heteroaromatic
group adjoining the C−H bond, can be converted as well.
The electronic nature of the aryl ring affects the yield to
some extent but has little influence on the regioselectivity (2j
and 2l). The insertion into the methine C−H bond is much
more favored than the methylene C−H bond (2q), whereas a
modest selectivity was observed between the benzyl group
and the methyl group (2p).15 An inferior result was obtained
for N-phenyl substrates 1m, 1n, and 1o, which need to be
treated at a higher temperature to guarantee an acceptable
yield. A higher temperature are also required for the
amination of the unactivated C(sp3)−H bond (2r−u).
Besides 3,3-disubstituted imidazolinones, α-monoalkyl-sub-
stituted 1aa and 1ab also reacted in the same way to give the
corresponding imidazolinone products 2aa and 2ab in good
yield. However, this protocol failed when employed to
prepare compounds 2x, 2y, 2z, and 2ac. Overall, these results
are comparable to our previous findings, but the milder
conditions render the current protocol more attractive in
practical synthesis.
a
Table 1. Screening of the Reaction Conditions
Our previous study showed that the unreactiveness of 1x
and 1y could be solved by adding Boc2O into the reaction
system.15 Thus a modified protocol with the addition of 1.2
equiv of Boc2O was employed to engender the desired
cyclization. As expected, Boc-protected imidazolinones 3x, 3y,
and 3ac were generated in good yield under the indicated
conditions (Scheme 3).
The standard conditions were also applied to compounds 4
and 5, which are analogous in structure to compound 1a. As
shown in Scheme 4, different results were obtained for these
two substrates: Whereas 5 can be transformed into the
cyclization product 7 in high yield, the reaction did not occur
for 4.
Intramolecular C−H amination of aliphatic azides con-
stitutes an effective approach toward structurally important
pyrrolidines. Several different iron complexes10−13 have been
used to engender this transformation. To see if [Fe(dpbz)]-
Cl2 could also catalyze the cyclization of simple aliphatic
azides, we subjected compounds 8−14 to the present
conditions. As shown in Table 2, these compounds reacted
smoothly under the indicated conditions when Boc2O was
used, affording the corresponding pyrrolidines in good yield.
Iron-catalyzed C(sp3)−H amination of azides is believed to
proceed via a radical process that involves a high-spin ferric
iminyl or imido radical complex as the intermediate.9,10 This
mechanism might also operate for the present [Fe(dpbz)]Cl2-
catalyzed reactions (Scheme 5). This hypothesis is supported
by our kinetic isotopic experiment with 1m-d and 8-d, which
b
entry [Fe(II)] (mol %)
solvent
temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
Cat-1 (5)
Cat-1 (5)
Cat-1 (5)
Cat-1 (5)
Cat-1 (1)
Cat-1 (10)
Cat-1 (20)
Cat-2 (5)
Cat-3 (5)
Cat-1 (5)
Cat-1 (5)
Cat-1 (5)
Cat-1 (5)
Cat-1 (5)
Cat-1 (5)
Cat-1 (5)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
DCE
DBE
PhCl
toluene
MeCN
DMF
40
40
50
25
40
40
40
40
40
40
40
40
40
40
40
40
12
24
12
12
12
12
12
12
12
24
24
24
24
24
24
24
89
99
98
45
52
93
93
30
71
61
75
75
trace
9
10
11
12
13
14
15
16
c
c
d
18
50
trace
a
Reactions were performed on a 0.2 mmol scale in 2 mL of solvent.
Isolated yield. Most of 1a was recovered. 80% of 1a was recovered.
DCE: 1,2-dichloroethane; DBE: 1,2-dibromoethane.
b
c
d
B
https://dx.doi.org/10.1021/acs.orglett.0c00308
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
g
Scheme 2. Scope of the Reaction
a
b
c
1
Reaction was conducted on a 5.0 mmol scale in 25 mL of CH2Cl2. Ratio was determined by H NMR. Reaction was conducted at 60 °C.
d
e
f
g
Reaction was conducted at 80 °C. Reaction was conducted at 65 °C. With most of the reactant recovered. Reactions were conducted on a 0.2
mmol scale at 40 °C unless otherwise specified. The yields are isolated yields.
gave kH/kD values of 5.2 and 6.7 for these two compounds,
respectively (Scheme 6). These values are close to the
Scheme 3. Boc2O-Facilitated Reactions of 1x, 1y, and 1ac
Scheme 6. Kinetic Isotopic Experiment
Scheme 4. Scope of the Reaction 2
reported ones.10a,15 Moreover, the result of the radical clock
experiment (Scheme 7) also accords with the previous
reports. The fact that no ring-opening products were formed
in the case of 1ad reflects a fast radical rebound step. Apart
from this scenario, it should be noted that these results are
also consistent with a mechanism of direct nitrene insertion
into the C−H bond.
Scheme 5. Plausible Mechanism
Scheme 7. Radical Clock Experiment
C
https://dx.doi.org/10.1021/acs.orglett.0c00308
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
University, Lanzhou, Gansu 730000, China; orcid.org/
0000-0002-3131-3080; Email: yuwei@lzu.edu.cn
Table 2. [Fe(dpbz)]Cl2-Catalyzed Reactions of Aliphatic
Azides
a
Authors
Siyu Liang − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou, Gansu 730000, China
Xiaopeng Zhao − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou, Gansu 730000, China
Tonghao Yang − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou, Gansu 730000, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00308
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(no. 21772077) and the State Key Laboratory of Applied
Organic Chemistry for financial support.
REFERENCES
■
(1) For reviews, see: (a) Davies, H. M. L.; Manning, J. R. Nature
2008, 451, 417−424. (b) Collet, F.; Dodd, R. H.; Dauban, P. Chem.
Commun. 2009, 5061−5074. (c) Dequirez, G.; Pons, V.; Dauban, P.
Angew. Chem., Int. Ed. 2012, 51, 7384−7395. (d) Suarez, A. I. O.;
Lyaskovskyy, V.; Reek, J. N. H.; van der Vlugt, J. I.; de Bruin, B.
Angew. Chem., Int. Ed. 2013, 52, 12510−12529. (e) Shimbayashi, T.;
Sasakura, K.; Eguchi, A.; Okamoto, K.; Ohe, K. Chem. - Eur. J. 2018,
25, 3156−3180. (f) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017,
117, 9247−9301.
a
Reaction was performed on a 0.2 mmol scale in 2 mL of CH2Cl2
with 5 mol % of Cat-1 and 1.2 equiv of Boc2O under an argon
atmosphere. Reaction time: 24 h. The reaction temperature was 65 °C
unless otherwise indicated. Isolated yield. Reaction temperature was
b
c
80 °C.
(2) (a) Stokes, B. J.; Driver, T. G. Eur. J. Org. Chem. 2011, 2011,
4071−4088. (b) Roizen, J. L.; Harvey, M. E.; Du Bois, J. Acc. Chem.
Res. 2012, 45, 911−922. (c) Jeffrey, J. L.; Sarpong, R. Chem. Sci.
2013, 4, 4092−4106. (d) Chu, J. C. K.; Rovis, T. Angew. Chem., Int.
Ed. 2018, 57, 62−101.
In summary, we have demonstrated that the Fe(II)−
phosphine complex [Fe(dpbz)]Cl2 is an competent catalyst
for the intramolecular C(sp3)−H amination of organic azides.
A variety of differently substituted α-azido amides can be
converted to the corresponding imidazolinones by the
catalysis of [Fe(dpbz)]Cl2. Compared with the previously
used catalytic system of FeCl2 and β-diketiminate, [Fe-
(dpbz)]Cl2 performed better in that the reaction can be
realized under milder conditions at a lower catalyst loading
level. Moreover, it is also capable of promoting the
cyclization of aliphatic azides in the presence of Boc2O.
Considering the wide applications of chiral phosphine ligands
in asymmetric synthesis, we hope that a suitable chiral iron−
phosphine complex can be found to enable the enantiose-
lective C(sp3)−H amination of azides.
(3) (a) Jiao, J.; Murakami, K.; Itami, K. ACS Catal. 2016, 6, 610−
633. (b) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017, 117, 9247−
9301.
(4) (a) Yuan, S.-W.; Han, H.; Li, Y.-L.; Wu, X.; Bao, X.; Gu, Z.-Y.;
Xia, J.-B. Angew. Chem., Int. Ed. 2019, 58, 8887−8892. (b) Qin, J.;
Zhou, Z.; Cui, T.; Hemming, M.; Meggers, E. Chem. Sci. 2019, 10,
3202−3207.
(5) (a) Zhang, L.; Deng, L. Chin. Sci. Bull. 2012, 57, 2352−2360.
(b) Wang, P.; Deng, L. Chin. J. Chem. 2018, 36, 1222−1240.
̈
(c) Plietker, B.; Roske, A. Catal. Sci. Technol. 2019, 9, 4188−4197.
(d) Liu, Y.; You, T.; Wang, T.; Che, C.-M. Tetrahedron 2019, 75,
130607.
(6) (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. (h) Baek, Y.; Betley, T. A. J. Am. Chem. Soc. 2019, 141, 7797−
7806. (i) Baek, Y.; Hennessy, E. T.; Betley, T. A. J. Am. Chem. Soc.
2019, 141, 16944−16953.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00308.
■
sı
General experimental procedures, characterization data,
1
and copies of H NMR and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Wei Yu − State Key Laboratory of Applied Organic Chemistry,
College of Chemistry and Chemical Engineering, Lanzhou
D
https://dx.doi.org/10.1021/acs.orglett.0c00308
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(7) (a) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297−
̈
368. (b) Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem., Int. Ed. 2005, 44, 5188−5240. (c) Organic Azides: Syntheses
̈
and Applications; Brase, S., Banert, K., Eds.; John Wiley & Sons:
Chichester, U.K., 2010.
(8) (a) Intrieri, D.; Zardi, P.; Caselli, A.; Gallo, E. Chem. Commun.
2014, 50, 11440−11453. (b) Shin, K.; Kim, H.; Chang, S. Acc.
Chem. Res. 2015, 48, 1040−1052.
(9) (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.
(10) (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.
(11) (a) Thacker, N. C.; Lin, Z.; Zhang, T.; Gilhula, J. C.; Abney,
C. W.; Lin, W. J. 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.
(12) 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.
(13) Shing, K.-P.; Liu, Y.; Cao, B.; Chang, X.-Y.; You, T.; Che, C.-
M. Angew. Chem., Int. Ed. 2018, 57, 11947−11951. (b) Du, Y.-D.;
Xu, Z.-J.; Zhou, C.-Y.; Che, C.-M. Org. Lett. 2019, 21, 895−899.
(14) Yang, T.; Fan, X.; Zhao, X.; Yu, W. Org. Lett. 2018, 20,
1875−1879.
(15) (a) Zhao, X.; Liang, S.; Fan, X.; Yang, T.; Yu, W. Org. Lett.
2019, 21, 1559−1563. (b) Correction: Zhao, X.; Liang, S.; Fan, X.;
Yang, T.; Yu, W. Org. Lett. 2020, DOI: 10.1021/acs.orglett.0c00658.
(16) A similar ruthenium-catalyzed enantioselective intramolecular
C(sp3)−H amination of 2-azidoacetamides was reported by
Meggers. See: Zhou, Z.; Chen, S.; Qin, J.; Nie, X.; Zheng, X.;
Harms, K.; Riedel, R.; Houk, K. N.; Meggers, E. Angew. Chem., Int.
Ed. 2019, 58, 1088−1093.
(17) The intramolecular C(sp3)−H amination has also been
realized by using Bu4N[Fe(CO)3(NO)] as a catalyst. Alt, I. T.;
Guttroff, C.; Plietker, B. Angew. Chem., Int. Ed. 2017, 56, 10582−
10586.
(18) Yang, T.; Lin, Y.; Yang, C.; Yu, W. Green Chem. 2019, 21,
6097−6102.
(19) (a) Barclay, J. E.; Leigh, G. J.; Houlton, A.; Silver, J. J. Chem.
Soc., Dalton Trans. 1988, 2865−2870. (b) Bedford, R. B.; Huwe, M.;
Wilkinson, M. C. Chem. Commun. 2009, 600−602. (c) Kumar, V.
P.; Babu, V. S.; Yahata, K.; Kishi, Y. Org. Lett. 2017, 19, 2766−2768.
E
https://dx.doi.org/10.1021/acs.orglett.0c00308
Org. Lett. XXXX, XXX, XXX−XXX