Intramolecular Csp3-H/C-C bond amination of alkyl azides for the selective synthesis of cyclic imines and tertiary amines

Article abstract of DOI:10.1039/c9sc05522c

The intramolecular Csp³-H and/or C-C bond amination is very important in modern organic synthesis due to its efficiency in the construction of diversified N-heterocycles. Herein, we report a novel intramolecular cyclization of alkyl azides for the synthesis of cyclic imines and tertiary amines through selective Csp³-H and/or C-C bond cleavage. Two C-N single bonds or a CN double bond are efficiently constructed in these transformations. The carbocation mechanism differs from the reported metal nitrene intermediates and therefore enables metal-free and new transformation.

Full text of DOI:10.1039/c9sc05522c

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Intramolecular Csp3-H/C-C Bond Amination of Alkyl Azides for the
Selective Synthesis of Cyclic Imines and Tertiary Amines
Received 00th January 20xx,
Accepted 00th January 20xx
Xiaojin Wen,a,§ Xinyao Li,a,§ Xiao Luo,a Weijin Wang,a Song Song*a,b and Ning Jiao*a
The intramolecular Csp3-H and/or C-C bond amination is very important in modern organic synthesis due to its efficiency in
construction of diversified N-heterocycles. Herein, we report a novel intramolecular cyclization of alkyl azides for the
synthesis of cyclic imines and tertiary amines through selective Csp3-H and/or C-C bond cleavage. Two C-N single bonds or
a C=N double bond are efficiently constructed in these transformations. The carbocation mechanism differentiates from
the reported metal nitrene intermediates and therefore enables the metal-free and new transformation.
DOI: 10.1039/x0xx00000x
www.rsc.org/
amination of alkyl azides catalyzed by iron catalyst (Scheme
1b).13a The groups of van der Vlugt,13c Lin,13d,e de Bruin,13c,f
and Chi13g independently developed the same elegant
Introduction
N-Heterocycles are undoubtedly important chemicals in organic
synthesis, and have been considered as key functionality
regulators in pharmaceuticals.1 The intramolecular nitrogen-
insertion into Csp3-H and/or C-C bond provides efficient
approach to N-heterocycles.2-5 The groups of Aubé4 and
Pearson5 pioneeringly developed the intramolecular Schmidt
reactions2 and made significant achievements for various N-
heterocycles synthesis.3 The earliest intramolecular aliphatic C-
N bond formation named Hofmann-Loffler-Freytag reaction5
always started from unstable halogenated amines to construct
N-heterocycles. Over the past two decades, the aliphatic C-H
amination has achieved great progress via C-H activation
strategy.6 However, most of these reactions required electron
withdrawing directing groups and delivered amide products
(Scheme 1a). Beginning with Breslow’s pioneering work,7
metal-nitrene strategy was successfully applied in
intramolecular Csp3-H bond N-insertion, providing elegant
approaches to amides bearing N-H bond (Scheme 1a).8 Thus,
the development of direct aliphatic C-H/C-C amination is still
highly desirable.
intramolecular cyclization of alkyl azides by iron, palladium or
cobalt catalysis to deliver N-Boc heterocycles (Scheme 1b), in
which the involved nitrene type intermediates required equivalent
Boc2O reagent to liberate the active catalyst to complete the catalytic
circle (Scheme 1b). Despite the advances of above strategies
(Scheme 1a-b), these intramolecular aliphatic amination/amidation
always delivered N-carbonyl or sulfonyl heterocycles with the
formation of one C-N single bond.
Inspired by these results, we speculated that the oxidative
generation of carbocation
A may trigger the formation of cyclic
intermediate (Scheme 1c), which may undergo other
B
transformations in the absence of transition-metal catalysts and
provides opportunity for new products. Herein, we described a
novel intramolecular nitrogen-insertion into Csp3-H and/or C-C
Organic azides are synthetically useful in drug discovery,
bioconjugation and material science.9 Although the
intramolecular Csp3-H bond amination/amidation of aryl
azides10 and sulfonyl azides11 has achieved great progress, the
corresponding transformation of alkyl azides12 were rarely
developed until recent results.13 In 2013, Betley and coworkers
pioneeringly demonstrated intramolecular aliphatic C-H
a.State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, China.
b.State Key Laboratory of Drug Research, Shanghai Institute of Materia Medical,
Chinese Academy of Sciences, Shanghai 201203, China.
* E-mail: ssong@bjmu.edu.cn; jiaoning@pku.edu.cn
These authors contributed equally to this work.
§
Scheme 1 Intramolecular N-insertion of Csp3-H bond.
† Electronic Supplementary Information (ESI) available: Characterization data and
experimental procedures. See DOI: 10.1039/x0xx00000x
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bond of alkyl azides to deliver cyclic imines and tertiary amines We explored the generality of this intramolecular Csp3-H nitrogen-
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DOI: 10.1039/C9SC05522C
(Scheme 1c). The aliphatic C-H or C-C bond was selectively insertion for δ-aryl alkyl azides under standard reaction conditions
cleaved with the efficient formation of two C-N single bonds or (Table 2). Substrates bearing electron-donating substituents (MeO,
a C=N double bond.
tBu, PhO) at the aryl ring worked smoothly to afford the
corresponding cyclic imines 2c-e in good yields. The electron-
withdrawing substituents (F, Cl) caused low reactivity, resulting
pyrrolines 2f-g in diminished yields (26-31%). Substituents at the
meta or ortho position of the arene rings 1h-j slightly affected the
efficiency. Besides arenes, the heteroaryl azide 2-(4-
azidobutyl)thiophene 1k was transformed to 2k in 32% yield. The
substituents on the alkyl chain influenced this reaction slightly (2l-o).
Results and discussion
Table 1 Optimization of the reaction conditions.a
The cyclic imines
2 were easily converted to diversified
heterocycles.15 Compared to the well-established approaches to
cyclic imines, the present intramolecular N-insertion protocol
features mild conditions and high atom economy.
Table 2 Nitrogenation of alkyl azides to imines. a
a Reaction conditions: 1a (0.3 mmol), oxidant (0.36 mmol) and acid (0.2 mL)
b
in solvent (0.5 mL) at 60 oC for 12 h. Yield determined by 1H NMR
spectroscopy with dibromomethane as an internal standard. c Performed with
d
e
TFA (0.4 mL). Isolated yields. Performed at room temperature. DDQ =
2,3-dichloro-5,6-dicyano-1,4-benzoquinone, CAN cerium ammonium
nitrate, TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, NHPI N-
=
=
=
hydroxyphthalimide, PIDA = phenyliodine diacetate, TFA = trifluoroacetic
acid, MsOH = methanesulfonic acid, TfOH = trifluoromethanesulfonic acid,
TCE = 1,1,2,2-tetrachloroethane.
a Reaction conditions: 1 (0.3 mmol), DDQ (0.36 mmol) and TFA (0.4 mL) in
b
c
TCE (0.5 mL) at 60 oC for 12 h. Isolated yields. Performed at 80 oC.
Performed with TFA (0.2 mL) at room temperature.
According to our previous elements incorporation reactions through
the carbocation intermediates generated in situ with DDQ oxidant,14
we chose azide 1a as the model substrate to investigate our
speculation. As expected, dihydropyrrole 2a was obtained in 75%
In order to synthesize six-membered cyclic imine, we conducted
the reaction of alkyl azide 3a under standard condition. However, the
target imine product 4a was not detected (eq 1). We conducted the
capture experiment by the addition of benzoyl chloride to the
reaction of 3a (eq 2). Aldehyde 5a and amide 6 were obtained in
77% and 66% yields, respectively (eq 2), which indicated that the
azide 3a was converted to amine via an imine cation intermediate
and a hydrolysis process (for detailed mechanism, see Scheme 2 and
3).
o
yield in the presence of DDQ and TFA at 60 C (Table 1, entry 1).
Two C-H bonds were cleaved and a C=N double bond was
constructed along with the release of N2 in this case. TEMPO or
CAN as the oxidant gave inferior yields (entries 2-3), while PIDA or
NHPI could not execute the conversion of 1a to 2a (entries 4-5). The
chlorinated solvent afforded better yields than that of other solvents
such as DMSO, toluene, or MeCN (entries 6-9), and the reaction
delivered the highest yield in TCE (entry 9). The pKa of acids
influenced the reaction strongly (entries 10-12). 2a was obtained in
only 10% yield in the presence of acetic acid (entry 10), while
MsOH or TfOH failed to facilitate this transformation (entries 11-
12). Treatment of 1a with 0.4 mL of TFA afforded 2a in satisfactory
73% isolated yield (entry 13). Lowering temperature was hampered
to the reactivity (entry 14).
2 | J. Name., 2012, 00, 1-3
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On the basis of this result, we investigated the one-pot reaction deprotonation with the release of N2 to afford cyclic imine 2, while
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of alkyl azide 3 with DDQ and TFA followed by in situ reduction. the six-membered ring intermediate D underDgoOeI:s110,.210-a3l9k/yCl9mSCi0g5ra5t2i2oCn
We were delighted to find that the corresponding cyclic tertiary to generate the imine cation E, which is sequentially reduced to
amine 7a was obtained in 55% yield (Table 3). The substituent on deliver tertiary amine 7.
the arene slightly influenced the yield and a series of N-Bn
pyrrolidines were synthesized in moderate yields. The azide
substrates bearing alkyl substituents also smoothly delivered benzyl-
substituted 7h or pyrrolidine 7i in moderate yield. In addition,
naphthalene, thiophene, dibenzofuran and dibenzothiophene were all
well tolerated to afford cyclic tertiary amines 7j-m in 33-81% yields.
It is noteworthy that the transformation of 3 to 7 with releasing
nitrogen as the only by-product, is thus high atom-economic.
Moreover, the present strategy cleaves the C(sp3)-C(sp3) bond16
without strained rings or assisted functional groups. Besides
Scheme 2 Proposed mechanism.
pyrrolidine, piperidine derivative 7n also could be synthesized by the
intramolecular N-insertion of alkyl azide 3n. Unfortunately, the
present strategy could not be applied in the construction of seven or
eight-membered N-heterocycles.
To further understand the mechanism, we performed preliminary
DFT calculation into the model reaction of alkyl azides 1 and 3 with
DDQ and TFA (Scheme 3).17 We first studied the oxidation of 1 at
the benzylic position by DDQ with TFA through O-attack hydride
transfer pathway, which is the most thermodynamically favorable
Table 3 Nitrogenation of alkyl azides to tertiary amines.a
pathway in some similar cases.18 The hydride transfer from
1 to
the complex of DDQ and TFA through TS1 requires Gibbs free
energy barrier of 28.0 kcal mol-1 to form the benzylic
carbocation intermediate A1 and DDQH-TFA- anion, which
could be stabilized by another TFA molecule to afford DDQ-
-
2H and H(CF3CO2)2 species. Subsequently, the azide moiety
would attack the formed carbocation in A1 to generate five-
membered ring C, which is exothermic by 19.2 kcal mol-1. In the
most stable conformation of C, the phenyl group on the equatorial
bond performs a small torsion angle (-24.4o) with azide moiety,
while the benzylic hydrogen and alkyl group has big dihedral angles
(95.4o and -150.0o, respectively) with azide moiety. Therefore, the
following Schmidt rearrangement2 of C with the concerted release of
N2 and hydrogen or alkyl shift is potentially feasible through
antiperiplanar migration. The Schmidt rearrangement with 1,2-H
shift through the antiperiplanar transition state TS2 with free energy
barrier of 16.8 kcal mol-1 gives 2-H. The barrier of 1,2-alkyl shift to
imine cation E1 through TS3 (ΔG⧧ = 21.7 kcal mol-1) is much higher
than 1,2-H shift pathway.
Alternatively, the hydride transfer from
DDQ and TFA through TS4 requires Gibbs free energy barrier
of 26.6 kcal mol-1 to form the benzylic carbocation A3
The
3 to the complex of
.
azide moiety is facile to attacks the intramolecular carbocation to
generate six-membered ring D, which is exothermic by 16.6 kcal
mol-1. In the most stable conformation of D, the dihedral angle of
azide moiety with the alkyl group increases to -159.5o, while the one
with hydrogen decreases to 84.2o. This is likely to provide the
advantage for 1,2-alkyl shift. The following Schmidt rearrangement
of D including 1,2-H shift through TS5 requires free energy barrier
of 15.3 kcal mol-1 to give 4-H. In contrast with C, D undergoes 1,2-
a Reaction conditions: 3 (0.3 mmol), DDQ (0.36 mmol) and TFA (0.2 mL) in
TCE (0.5 mL) at room temperature for 12 h. Isolated yields. b Performed with
TFA (0.4 mL) at 60 oC. c Performed at 60 oC.
Based on the above experiments, we proposed the possible
mechanism of the reaction (Scheme 2). The oxidation of alkyl azides
1 and 3 at the benzylic position by DDQ with TFA provides benzylic
cation intermediate A, which is attacked by the azide group to
generate cyclic intermediate B. In the most stable conformation of B,
the aryl group should stand on the equatorial bond, which performs a
small torsion angle with azide moiety. As a result, the following
Schmidt rearrangement of B with the concerted release of N2 and
aryl shift is unfavorable through periplanar migration, while
hydrogen or alkyl shift is potentially feasible through antiperiplanar
migration. The five-membered ring species C undergoes the
alkyl shift through TS6 with free energy barrier of 14.4 kcal mol-1
,
which is favorable than 1,2-H shift pathway, indicating that 1,2-alkyl
shift pathway becomes predominant. Reviewing the whole energy
profile, it is revealed that the oxidation with hydride transfer is the
rate-determining step, while the chemoselectivity in the
nitrogenation of alkyl azides is essentially controlled by the
conformation of cyclic intermediate and the ring-side in the Schmidt
rearrangement process. The experimental observed electronic effects
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on the Ar group is consistent with first oxidation step with hydride Financial support from the National NatuVriaewl ArtSiclceiOennlcinee
DOI: 10.1039/C9SC05522C
transfer as the rate-determining step (see ESI for details).
Foundation of China (Nos. 21632001, 21602005, 81821004),
and the Drug Inno-vation Major Project (2018ZX09711-001),
Peking University (No. PKU2020PKYZX004), Major changes
in the central level support projects (2060302), and the Open
Research Fund of Shanghai Key Laboratory of Green
Chemistry and Chemical Processes are greatly appreciated. We
thank Xiaoxue Yang in this group for reproducing the results of
2m and 7l
.
Notes and references
1
(a) A. Deiters and S. F. Martin, Chem. Rev., 2004, 104, 2199-
2238; (b) R. D. Taylor, M. MacCoss and A. D. G. Lawson, J.
Med. Chem., 2014, 57, 5845-5859.
2
(a) R. F. Schmidt, Ber., 1924, 57, 704-706; (b) P. A. S. Smith,
J. Am. Chem. Soc., 1948, 70, 320-323; (c) L. H. Briggs, G. C.
De Ath and S. R. Ellis, J. Chem. Soc., 1942, 61-63; (d) H.
Wolfe, Org. React., 1946, 3, 307-336; (e) P. A. S. Smith,
Molecular Rearrangements, John Wiley & Sons, New York,
1963; (f) R. A. Abramovich and E. P. Kyba, The Chemistry of
the Azido Group, John Wiley & Sons, London, 1971; (g) A.
Wrobleski, T. C. Coombs, C. W. Huh, S.-W. Li and J. Aubé,
Org. React., 2012, 78, 1-320; (h) M. Szostak and J. Aubé,
Chem. Rev., 2013, 113, 5701-5765.
3
(a) J. Aubé and G. L. Milligan, J. Am. Chem. Soc., 1991, 113,
8965-8966; (b) J. Aubé, G. L. Milligan and C. J. Mossman, J.
Org. Chem., 1992, 57, 1635-1637; (c) V. Gracias, G. L.
Milligan and J. Aubé, J. Am. Chem. Soc., 1995, 117, 8047-
8048; (d) G. L. Milligan, C. J. Mossman and J. Aubé, J. Am.
Chem. Soc., 1995, 117, 10449-10459; (e) A. Wrobleski, K.
Sahasrabudhe and J. Aubé, J. Am. Chem. Soc., 2004, 126
,
5475-5481
4
5
(a) W. H. Pearson and J. M. Schkeryantz, Tetrahedron Lett.
1992, 33, 5291-5294; (b) W. H. Pearson, R. Walavalkar, J. M.
Schkeryantz, W. Fang and J. D. Blickensdorf, J. Am. Chem.
Soc. 1993, 115, 10183-10194.
For selected reviews of C-H amination, see: (a) H. M. L.
Davies and M. S. Long, Angew. Chem., Int. Ed., 2005, 44
,
3518-3520; (b) T. W. Lyons and M. S. Sanford, Chem. Rev.,
2010, 110, 1147-1169; (c) J. L. Jeffrey and R. Sarpong, Chem.
Scheme 3 Energy profile for the DDQ-mediated amination of alkyl
azides 1 and 3.
Sci., 2013,
and W. Zhang, Chem. Rev., 2015, 115, 1622-1651; (e) J. J.
Topczewski and M. S. Sanford, Chem. Sci., 2015, , 70-76; (f)
4, 4092-4106; (d) X.-X. Guo, D.-W. Gu, Z. Wu
6
Y. Park, Y. Kim and S. Chang, Chem. Rev., 2017, 117, 9247-
9301; (g) J. He, M. Wasa, K. S. L. Chan, Q. Shao and J.-Q.
Yu, Chem. Rev., 2017, 117, 8754-8786; (h) F. Collet, R. H.
Dodd and P. Dauban, Chem. Commun., 2009, 5061-5074.
(a) A. W. Hofmann, Ber. Dtsch. Chem. Ges., 1883, 16, 558-
Conclusions
In summary, we have demonstrated
a
novel metal-free
intramolecular Csp3-H/C-C amination of alkyl azides for the
synthesis of cyclic imines and tertiary amines. Two C-N single
bonds or a C=N double bond are efficiently constructed in these
transformations through the highly selective benzyl Csp3-H or C-C
bond cleavage. The mechanistic studies and DFT calculation
indicate a carbon cation pathway for this novel protocol. The present
chemistry not only provides a new approach to N-heterocycles, but
also expands the transformation and application of C-H/C-C
6
560; (b) K. Lçffler and C. Freytag, Chem. Ber., 1909, 42
,
3427-3431; (c) S. Lang and J. A. Murphy, Chem. Soc. Rev.,
2006, 35, 146-156; (d) P. S. Baran, K. Chen and J. M. Richter,
J. Am. Chem. Soc., 2008, 130, 7247-7249; (e) C. Martínez
and K. Muñiz, Angew. Chem., Int. Ed., 2015, 54, 8287-8291;
(f) E. A. Wappes, S. C. Fosu, T. C. Chopko and D. A. Nagib,
Angew. Chem., Int. Ed., 2016, 55, 9974-9978; (g) P. Becker,
T. Duhamel, C. J. Stein, M. Reiher and K. Muñiz, Angew.
Chem., Int. Ed., 2017, 56, 8004-8008; (h) S. Liu, J. Li, D.
Wang, F. Liu, X. Liu, Y. Gao, J. Dai, X. Cheng, Chin. J.
Chem. 2019, 37, 570-574.
amination in organic synthesis
.
Acknowledgements
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ARTICLE
7
(a) R. Breslow and S. H. Gellman, J. Chem. Soc. Chem.
Comm., 1982, 1400-1401; (b) R. Breslow and S. H. Gellman,
J. Am. Chem. Soc., 1983, 105, 6728-6729.
(a) J. L. Roizen, M. E. Harvey and J. Du Bois, Acc. Chem.
Res., 2012, 45, 911-922; (b) S.-M. Au, J.-S. Huang, W.-Y. Yu,
Dydio, H. M. Key, H. Hayashi, D. S. Clark and VJi.ewF.ArHticalertOwnliinge,
J. Am. Chem. Soc., 2017, 139, 1750-17D5O3.I: 10.1039/C9SC05522C
12 (a) J. E. Forsee and J. Aubé, J. Org. Chem. 1999, 64, 4381-
4385; (b) B. T. Smith, V. Gracias and J. Aubé, J. Org. Chem.,
2000, 65, 3771-3774; (c) D. J. Gorin, N. R. Davis and F. D.
Toste, J. Am. Chem. Soc., 2005, 127, 11260-11261; (d) A.
Kapat, E. Nyfeler, G. T. Giuffredi and P. Renaud, J. Am.
Chem. Soc., 2009, 131, 17746-17747; (e) M. Szostak and J.
Aubé, J. Am. Chem. Soc., 2010, 132, 2530-2531; (f) R. Liu, O.
Gutierrez, D. J. Tantillo and J. Aubé, J. Am. Chem. Soc., 2012,
134, 6528-6531; (g) H. F. Motiwala, C. Fehl, S.-W. Li, E.
8
W.-H. Fung and C.-M. Che, J. Am. Chem. Soc., 1999, 121
,
9120-9132; (c) E. Milczek, N. Boudet and S. Blakey, Angew.
Chem., Int. Ed., 2008, 47, 6825-6828; (d) M. E. Harvey, D. G.
Musaev and J. Du Bois, J. Am. Chem. Soc., 2011, 133
,
17207-17216; (e) S. M. Paradine and M. C. White, J. Am.
Chem. Soc., 2012, 134, 2036-2039; (f) J. W. Rigoli, C. D.
Weatherly, J. M. Alderson, B. T. Vo and J. M. Schomaker, J.
Am. Chem. Soc., 2013, 135, 17238-17241; (g) J. M. Alderson,
A. M. Phelps, R. J. Scamp, N. S. Dolan and J. M. Schomaker,
J. Am. Chem. Soc., 2014, 136, 16720-16723; (h) S. M.
Paradine, J. R. Griffin, J. Zhao, A. L. Petronico, S. M. Miller
Hirt, P. Porubsky and J. Aubé, J. Am. Chem. Soc., 2013, 135
,
9000-9009; (h) X. Sun, C. Gao, F. Zhang, Z. Song, L. Kong,
X. Wen and H. Sun, Tetrahedron, 2014, 70, 643-649; (i) X.-J.
Wang, Y. Su, R. Li and P. Gu, J. Org. Chem., 2018, 83
5816-5824; (j) M. Charaschanya and J. Aubé, Nat. Commun.,
2018, , 934-942.
,
9
13 (a) E. T. Hennessy and T. A. Betley, Science, 2013, 340, 591-
595; (b) D. A. Iovan, M. J. T. Wilding, Y. Baek, E. T.
and M. C. White, Nat. Chem., 2015, 7, 987-994; (i) S. Y.
Hennessy and T. A. Betley, Angew. Chem., Int. Ed., 2017, 56
,
15599-15602; (c) B. Bagh, D. L. J. Broere, V. Sinha, P. F.
Kuijpers, N. P. van Leest, B. de Bruin, S. Demeshko, M. A.
Hong, Y. Park, Y. Hwang, Y. B. Kim, M.-H. Baik and S.
Chang, Science, 2018, 359, 1016-1021; (j) H. M. L. Davies
and J. R. Manning, Nature, 2008, 451, 417-424; (k) K. J.
Stowers, K. C. Fortner and M. S. Sanford, J. Am. Chem. Soc.,
2011, 133, 6541-6544; (l) C. G. Espino, P. M. Wehn, J. Chow
and J. Du Bois, J. Am. Chem. Soc., 2001, 123, 6935-6936; (m)
C. G. Espino, K. W. Fiori, M. Kim and J. Du Bois, J. Am.
Chem. Soc., 2004, 126, 15378-15379; (n) D. N. Zalatan and J.
Du Bois, J. Am. Chem. Soc., 2008, 130, 9220-9221.
Siegler and J. I. van der Vlugt, J. Am. Chem. Soc., 2017, 139
5117-5124; (d) N. C. Thacker, Z. Lin, T. Zhang, J. C. Gilhula,
C. W. Abney and W. Lin, J. Am. Chem. Soc., 2016, 138
,
,
3501-3509; (e) Z. Lin, N. C. Thacker, T. Sawano, T. Drake, P.
Ji, G. Lan, L. Cao, S. Liu, C. Wang and W. Lin, Chem. Sci.,
2018, 9, 143-151; (f) P. F. Kuijpers, M. J. Tiekink, W. B.
Breukelaar, D. L. J. Broere, N. P. van Leest, J. I. van der
Vlugt, J. N. H. Reek and B. de Bruin, Chem. - Eur. J., 2017,
23, 7945-7952; (g) K.-P. Shing, Y. Liu, B. Cao, X.-Y. Chang,
9
For selected reviews, see: (a) V. V. Rostovtsev, L. G. Green,
V. V. Fokin and K. B. Sharpless, Angew. Chem., Int. Ed.,
2002, 41, 2596-2599; (b) K. Shin, H. Kim and S. Chang, Acc.
Chem. Res., 2015, 48, 1040-1052; (c) S. Bräse, C. Gil, K.
Knepper and V. Zimmermann, Angew. Chem., Int. Ed., 2005,
44, 5188-5240; (d) E. Leemans, M. D’hooghe and N. De
Kimpe, Chem. Rev., 2011, 111, 3268-3333.
T. You and C.-M. Che, Angew. Chem., Int. Ed., 2018, 57
,
11947-11951; (h) D. L. J. Broere, B. de Bruin, J. N. H. Reek,
M. Lutz, S. Dechert and J. I. van der Vlugt, J. Am. Chem.
Soc., 2014, 136, 11574-11577; (i) D. L. J. Broere, N. P. van
Leest, B. de Bruin, M. A. Siegler and J. I. van der Vlugt,
Inorg. Chem., 2016, 55, 8603-8611; (j) N. P. van Leest, L.
Grooten, J. I. van der Vlugt and B. de Bruin, Chem. Eur. J.,
2019, 25, 5987-5993.
14 (a) C. Qin and N. Jiao, J. Am. Chem. Soc., 2010, 132, 15893-
15895; (b) F. Chen, C. Qin, Y. Cui and N. Jiao, Angew.
Chem., Int. Ed., 2011, 50, 11487-11491; (c) C. Qin, T. Shen,
C. Tang and N. Jiao, Angew. Chem., Int. Ed., 2012, 51, 6971-
6975; (d) J. Liu, X. Wen, C. Qin, X. Li, X. Luo, A. Sun, B.
10 (a) S. Murata, R. Yoshidome, Y. Satoh, N. Kato and H.
Tomioka, J. Org. Chem., 1995, 60, 1428-1434; (b) K. Sun, R.
Sachwani, K. J. Richert and T. G. Driver, Org. Lett., 2009, 11
3598-3601; (c) Q. Nguyen, K. Sun and T. G. Driver, J. Am.
Chem. Soc., 2012, 134, 7262-7265; (d) Q. Nguyen, T.
Nguyen and T. G. Driver, J. Am. Chem. Soc., 2013, 135, 620-
623; (e) O. Villanueva, N. M. Weldy, S. B. Blakey and C. E.
,
Zhu, S. Song and N. Jiao, Angew. Chem., Int. Ed., 2017, 56
,
11940-11944; (e) J. Liu, X. Qiu, X. Huang, X. Luo, C. Zhang,
J. Wei, J. Pan, Y. Liang, Y. Zhu, Q. Qin, S. Song and N. Jiao,
Nat. Chem., 2019, 11, 71-77; (f) Y. Liang, Y.-F. Liang, and N.
MacBeth, Chem. Sci., 2015,
6, 6672-6675; (f) I. T. Alt, C.
Jiao, Org. Chem. Frontiers 2015, 2, 403-415.
Guttroff and B. Plietker, Angew. Chem., Int. Ed., 2017, 56
,
,
15 (a) M. Ringwald, R. Sturmer and H. H. Brintzinger, J. Am.
Chem. Soc., 1999, 121, 1524-1527; (b) C. A. Figueira and P.
T. Gomes, Catal. Lett., 2015, 145, 762-768; (c) H. Karoui, C.
Nsanzumuhire, F. L. Le Moigne and P. Tordo, J. Org. Chem.,
1999, 64, 1471-1477.
10582-10586; (g) T. G. Driver, Org. Biomol. Chem., 2010,
8
3831-3846.
11 (a) J. V. Ruppel, R. M. Kamble and X. P. Zhang, Org. Lett.,
2007, , 4889-4892; (b) M. Ichinose, H. Suematsu, Y.
9
Yasutomi, Y. Nishioka, T. Uchida and T. Katsuki, Angew.
Chem., Int. Ed., 2011, 50, 9884-9887; (c) H. Lu, K. Lang, H.
16 For selected reviews of C-C cleavage, see: (a) C.-H. Jun,
Chem. Soc. Rev., 2004, 33, 610-618; (b) A. Dermenci, J. W.
Jiang, L. Wojtas and X. P. Zhang, Chem. Sci., 2016,
7, 6934-
Coe and G. Dong, Org. Chem. Front., 2014, 1, 567-581; (c) L.
6939; (d) H. Lu, H. Jiang, L. Wojtas and X. P. Zhang, Angew.
Chem., Int. Ed., 2010, 49, 10192-10196; (e) J. A. McIntosh, P.
Souillart and N. Cramer, Chem. Rev., 2015, 115, 9410-9464;
(d) M. Murakami and N. Ishida, J. Am. Chem. Soc., 2016, 138
,
S. Coelho, C. C. Farwell, Z. J. Wang, J. C. Lewis, T. R.
13759-13769; (e) M. Tobisu and N. Chatani, Chem. Soc. Rev.,
2008, 37, 300-307; (f) F. Chen, T. Wang and N. Jiao, Chem.
Rev., 2014, 114, 8613-8661; (g) X. Wu, C. Zhu, Chin. J.
Chem. 2019, 37, 171-182.
Brown and F. H. Arnold, Angew. Chem., Int. Ed., 2013, 52
,
9309-9312; (f) H. Lu, C. Li, H. Jiang, C. L. Lizardi and X. P.
Zhang, Angew. Chem., Int. Ed., 2014, 53, 7028-7032; (g) T.
K. Hyster, C. C. Farwell, A. R. Buller, J. A. McIntosh and F.
H. Arnold, J. Am. Chem. Soc., 2014, 136, 15505-15508; (h) P.
17 All of the geometry optimizations and frequency calculations
were performed with the M06-2X functional implemented in
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ARTICLE
Gaussian 09. All of the energies discussed in the paper are
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DOI: 10.1039/C9SC05522C
Gibbs free energies at the def2-TZVP basis set based on the
structures with the PCM solvation correction in DCE at the 6-
31+G(d,p)basis set. Computational details and references are
given in the ESI.
18 (a) B. Chan and L. Radom, J. Phys. Chem. A, 2007, 111
,
6456-6467; (b) X. Guo, H. Zipse and H. Mayr, J. Am. Chem.
Soc., 2014, 136, 13863-13873; (c) S. Yamabe, S. Yamazaki
and S. Sakaki, Int. J. Quantum Chem., 2015, 115, 1533-1542;
(d) A. S. K.-Tsang, A. S. K. Hashmi, P. Comba, M. Kerscher,
B. Chan and M. H. Todd, Chem. Eur. J., 2017, 23, 9313-9318;
(e) C. A. Morales-Rivera, P. E. Floreancig and P. Liu, J. Am.
Chem. Soc., 2017, 139, 17935-17944; (f) A. Gouranourimi, A.
Chipman, R. Babaahmadi, A. Olding, B. F. Yates and A.
Ariafard, Org. Biomol. Chem., 2018, 16, 9021-9029.
6 | J. Name., 2012, 00, 1-3
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A novel intramolecular cyclization of alkyl azides for the synthesis of cyclic imines and
tertiary amines has been developed. The aliphatic C-H or C-C bond was selectively cleaved
with the efficient formation of two C-N single bonds or a C=N double bond.
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