Copper-catalyzed redox-neutral C-H amination with amidoximes

Article abstract of DOI:10.1039/c3ob41871e

CuI-catalyzed reactions of N-alkylamidoximes afforded dihydroimidazoles via sp³ C-H amination. On the other hand, the reactions of N-benzoylamidoximes resulted in sp² C-H amination to form quinazolinones. The reaction mechanisms could be characterized as a redox-neutral radical pathway including a Cu(i)-Cu(ii) redox catalytic cycle. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob41871e

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Copper-catalyzed redox-neutral C–H amination
with amidoximes†
Cite this: Org. Biomol. Chem., 2014,
12, 42
Hui Chen and Shunsuke Chiba*
Received 12th September 2013,
Accepted 31st October 2013
DOI: 10.1039/c3ob41871e
www.rsc.org/obc
CuI-catalyzed reactions of N-alkylamidoximes afforded dihydro-
imidazoles via sp3 C–H amination. On the other hand, the reac-
tions of N-benzoylamidoximes resulted in sp2 C–H amination to
form quinazolinones. The reaction mechanisms could be charac-
terized as a redox-neutral radical pathway including a Cu(I)–Cu(II)
redox catalytic cycle.
Abundance of nitrogen-containing heterocycles (azahetero-
cycles) in biologically active alkaloids and pharmaceutical
drugs has stimulated synthetic chemists to develop a variety of
reactions enabling efficient construction of them.1,2 Among
these methodologies, intramolecular C–H amination offers
atom- and step-economical routes to access the azaheterocyclic
frameworks, and various sets of the strategies have recently
been exploited, especially with transition-metal catalysts.3
Our group has worked on the development of C–H oxi-
dation based on radical-mediated (non-nitrene-based) tactics,4
where we have recently made use of amidine derivatives for
Cu-catalyzed aliphatic C–H oxidation reactions towards the
synthesis of azaheterocycles.5,6 For example, we disclosed
Cu-catalyzed PhI(OAc)2-mediated C–H amination of N-alkyl
amidines for the synthesis of dihydroimidazoles (Scheme 1).5a
This strategy is initiated by the 1,5-H-radical shift of amidinyl
radical A oxidatively generated from the amidine, which
results in the formation of C-radical B. Further oxidation of
C-radical B leads to carbocation C that is subsequently ami-
nated to give the dihydroimidazole. However, the drawback of
this reaction is that it requires a stoichiometric use of PhI-
(OAc)2 to maintain the catalytic turnover, obviously because of
the redox nature of this strategy, needing two-electron oxi-
dation (for the generation of amidinyl radical A from the
amidine and the oxidation of transient C-radical B to carbo-
cation C) to realize the aliphatic C–H amination.
Scheme 1 Cu-catalyzed PhI(OAc)2-mediated C–H amination with ami-
dines (our previous work).
Scheme 2 Redox-neutral C–H amination with amidoximes (this work).
To develop an entirely catalytic system for the C–H amin-
ation, employment of amidoximes as a precursor of the amidi-
nyl radical A was envisioned.7 As shown in Scheme 2, the
reaction is initiated by reduction of the oxime N–O bond with
Cu(I) species, generating amidinyl radicals A along with Cu(II)
species.8 After the 1,5-H shift, the resulting C-radicals B are
oxidized to the carbocation C by the Cu(II)9 to result in the
formation of dihydroimidazole products and re-generation of
Cu(I) species. This reductive initiation–oxidative termination
sequence with amidoximes potentially enables redox-neutral
C–H amination.10–13
Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore 637371,
Singapore. E-mail: shunsuke@ntu.edu.sg; Fax: +65-67911961
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data of products, and copies of 1H and 13C NMR
spectra. See DOI: 10.1039/c3ob41871e
42 | Org. Biomol. Chem., 2014, 12, 42–46
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Table 1 Optimization of the reaction conditionsa
Table 2 Scope of the synthesis of dihydroimidazoles 2a,b
Entry
Cu salts (mol%)
Solvent
Time (h)
Yieldb (%)
1
2
3
CuCl (20)
CuBr (20)
CuI (20)
DMF
DMF
DMF
4
4
2
51
68
72
4
5
6
7
(CuOTf)2·C6H6 (10)
CuOAc (20)
CuTC (20)
CuI (20)
DMF
DMF
DMF
DMA
4
3.5
2
52
66
61
66
3
8
9
10
CuI (20)
CuI (20)
CuI (10)
DMSO
Toluene
Toluene
3
2
4
61
75
76 (77,c 74d)
a The reactions were carried out using 0.3 mmol of 1a in solvents
(0.1 M). Unless otherwise noted, the major isomer of amidoxime 1a
was utilized for this optimization. b Isolated yields. c The yield of 2a in
the reaction of the minor isomer of 1a. d The yield of 2a in the reaction
of the 1.3 : 1 mixture of major/minor isomers of oxime 1a. TC =
2-thiophene carboxylate. Bn = benzyl.
a The reactions were carried out using 0.3 mmol of 1 with CuI
(10 mol%) and K3PO4 (1 equiv.) in toluene (0.1 M) at 100 °C under an
Ar atmosphere. b Isolated yields were recorded above. c The reaction
was conducted with the corresponding O-pivaloyl oxime 1p.
With the hypothesis outlined in Scheme 2, our investigation
commenced with the reaction of amidoxime 1a for the con-
struction of dihydroimidazole 2a (Table 1). Amidoxime 1a was
synthesized by treatment of benzaldoxime with NCS followed
by the secondary amine (see the ESI† for more details) and
was obtained as a 1.7 : 1 mixture of E/Z isomers (the stereo- moiety (2k), and an indolyl part (2l) to afford the corres-
chemistry was not determined). First of all, the major isomer ponding dihydroimidazoles 2 in good yields, while the yield of
of oxime 1a was utilized for the optimization of the reaction C–H amination on non-benzylic dimethyl methine carbon was
conditions. Treatment of amidoxime 1a with a series of Cu(I) moderate (2m in 50% yield). Spirocyclic structures could be
salts as a catalyst (20 mol%) in the presence of K3PO4 in DMF nicely constructed by the present method (2n–p), while
resulted in the formation of 2a in moderate to good yields amination of
a non-benzylic adamantyl C–H bond (2p)
(entries 1–6) and the best yield of 2a was provided by CuI (72% resulted in moderate yield.
yield, entry 3). Screening of the solvents (entries 7–9) revealed
The reaction of oximes 1q and 1r with a secondary methyl-
that toluene is optimal for this transformation (entry 9). The ene C–H bond delivered aromatic imidazoles 3q (30% yield)
catalyst loading of CuI could be reduced to 10 mol% in and 3r (36% yield) as well as uncyclized amidine 4q (41%
toluene, giving 2a in 76% yield (entry 10). These optimized yields) and 4r (42% yield), respectively (Scheme 3-a). To
reaction conditions (10 mol% of CuI in toluene at 100 °C) were prevent the formation of imidazoles 3 presumably via oxidative
applicable to the minor isomer of amidoxime 1a as well as the aromatization of putative dihydroimidazole intermediates, the
1.3 : 1 mixture of major/minor isomers of 1a, affording com- reaction of N-acetylamidoxime 1s was examined (Scheme 3-b).
parable yields of dihydroimidazole 2a (77% and 74% yields, While dihydroimidazole 2s was isolated as expected, the yield
respectively).
of 2s was low (24% yield) and amide 5 was obtained in 57%
This CuI-catalyzed redox-neutral aliphatic C–H amination yield via C–N bond fission. In sharp contrast, the reaction of
was extended to various amidoximes 1 as compiled in Table 2. N-benzoyl amidoxime 6a produced quinazolinone 7a in 60%
The scope was first explored by varying the substituents R1, in yield via addition of the amidinyl radical A to the benzoyl part
which sterically hindered aromatic rings (2b, 2c) and both elec- (marked in green) (Scheme 3-c). This redox neutral sp2 C–H
tron-rich (2d) and -deficient (2e, 2f) ones as well as 3-pyridyl amination inspired us further to examine its scope and limit-
motif (for 2g) could be installed. A cyclohexyl group could be ation for the synthesis of substituted quinazolinones.
used as the R1, while the yield of dihydroimidazole 2h was
Optimization of the reaction conditions14 revealed that the
moderate (40% yield). The method allowed installing not only reactions of O-pivaloyl oximes 6b–h with 10 mol% of CuI in
a benzyl (Bn) but also n-butyl and phenyl groups (2i and 2j) as m-xylene at 130 °C were optimal for this quinazolinone for-
the substituent R2. The tertiary carbon aminated (marked in mation (Table 3). By varying substituents R1, benzene rings
blue) could possess a bulky isopropyl group (2i), a diphenyl bearing electron-donating and -withdrawing groups as well as
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happens to not only the ortho-carbon to the carbonyl (marked
in green, path a) but also the ipso-carbon (marked in purple,
path b via carbamoyl radical D), which resulted in the for-
mation of regioisomeric mixtures of quinazolinones 7 and 7′
(Scheme 4-a). We also observed the same cases when
Scheme 3 The reactions of amidoximes 1q, 1r, 1s, and 6a.
Table 3 Scope of the synthesis of quinazolinones 7a,b
a The reactions were carried out using 0.3 mmol of 6 with CuI
(10 mol%) and K3PO4 (1 equiv.) in m-xylene (0.1 M) at 130 °C under an
Ar atmosphere. b Isolated yields were recorded above.
a cyclohexyl motif could be installed (7b–7e). As R2, not only
benzyl and p-methoxybenzyl (for 7f) but also n-butyl and cyclo-
propyl units (7g, 7h) were introduced.
Previous precedents of the quinazolinone formation by
cyclization of the amidinyl radical to the benzoyl benzene
ring15,16 demonstrated that the addition of amidinyl radical A
Scheme 4 Formation of regioisomeric quinazolinones 7 and 7’.
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additional substituents R3 were put on the benzoyl benzene
rings. By installing para-substituents R3, the reactions provided
ortho-addition products 7i–7k as major products along with
minor ipso-addition products 7i′–7k′ regardless of the elec-
tronic nature of the substituents R3 (Scheme 4-b).17 On the
other hand, putting a methyl group at the ortho position (for
the reaction of 6l) rendered the ipso addition product 7l′ major
presumably because the helical sense of the C–C bond due to
the ortho methyl group made interaction between the amidinyl
radical and the ipso carbon smoother (path b) (Scheme 4-c). In
the case of N-2-naphthoylamidoxime 6m, the amination reac-
tion exclusively occurred with the ortho α-carbon (marked in
green) to give 7m in 79% yield (Scheme 4-d).
Res., 2012, 45, 911; (d) J. Du Bois, Org. Process Res. Dev.,
2011, 15, 758; (e) F. Collet, C. Lescot and P. Dauban, Chem.
Soc. Rev., 2011, 40, 1926; (f) D. N. Zalatan and J. Du Bois,
Top. Curr. Chem., 2010, 292, 347; (g) F. Collet, R. H. Dodd
and P. Dauban, Chem. Commun., 2009, 5061;
(h) M. M. Díaz-Requejo and P. J. Pérez, Chem. Rev., 2008,
108, 3379.
4 For recent examples of radical-mediated (non-nitrene-
based) aliphatic C–H amination reactions, see:
(a) Y. Amaoka, S. Kamijo, T. Hoshikawa and M. Inoue,
J. Org. Chem., 2012, 77, 9959; (b) Q. Michaudel, D. Thevenet
and P. S. Baran, J. Am. Chem. Soc., 2012, 134, 2547; (c) Z. Ni,
Q. Zhang, T. Xiong, Y. Zheng, Y. Li, H. Zhang, J. Zhang and
Q. Liu, Angew. Chem., Int. Ed., 2012, 51, 1244;
(d) R. T. Gephart III, D. L. Huang, M. J. B. Aguila,
G. Schmidt, A. Shahu and T. H. Warren, Angew. Chem., Int.
Ed., 2012, 51, 6488; (e) S. Sakagushi, T. Hirabayashi and
Y. Ishii, Chem. Commun., 2002, 516; (f) H. Togo, Y. Harada
and M. Yokoyama, J. Org. Chem., 2000, 65, 926.
5 (a) H. Chen, S. Sanjaya, Y.-F. Wang and S. Chiba, Org. Lett.,
2013, 15, 212; (b) Y.-F. Wang, H. Chen, X. Zhu and S. Chiba,
J. Am. Chem. Soc., 2012, 134, 11980.
6 For Cu-catalyzed oxidative transformation of N-alkenyl-
amidines for the synthesis of azaheterocycles, see:
(a) S. Sanjaya and S. Chiba, Org. Lett., 2012, 14, 5342;
(b) Y.-F. Wang, X. Zhu and S. Chiba, J. Am. Chem. Soc.,
2012, 134, 3679.
Conclusions
In summary, we have developed CuI-catalyzed redox neutral
sp3 and sp2 C–H amination reactions of readily available
N-alkyl- and N-benzoylamidoximes, affording dihydro-
imidazoles and quinazolinones, respectively. Application of
these catalytic redox-neutral radical strategies to intermole-
cular C–H amination is now under investigation in our
laboratory.
This work was supported by funding from Nanyang Techno-
logical University and the Singapore Ministry of Education
(Academic Research Fund Tier 2: MOE2012-T2-1-014).
7 Zard reported the generation of amidinyl radicals from
O-benzoyl amidoximes under the stannane-diazo initiator
system or the Ni-AcOH conditions, see: D. Gennet,
S. Z. Zard and H. Zhang, Chem. Commun., 2003, 1870.
8 For reports on single-electron-reduction of the oxime N–O
bonds with Cu(I) species, see: (a) M.-N. Zhao, H. Liang,
Z.-H. Ren and Z.-H. Guan, Synthesis, 2012, 1501;
(b) K. Tanaka, M. Kitamura and K. Narasaka, Bull. Chem.
Soc. Jpn., 2005, 78, 1659; (c) Y. Koganemaru, M. Kitamura
and K. Narasaka, Chem. Lett., 2002, 784; (d) J. Boivin,
A.-M. Schiano, S. Z. Zard and H. Zhang, Tetrahedron Lett.,
1999, 40, 4531; (e) J. Boivin, A.-M. Schiano and S. Z. Zard,
Tetrahedron Lett., 1992, 33, 7849.
9 J. K. Kochi, A. Bemis and C. L. Jenkins, J. Am. Chem. Soc.,
1968, 90, 4616.
10 For reviews on redox-neutral C–H functionalization, see:
(a) B. Peng and N. Maulide, Chem.–Eur. J., 2013, 19, 13274;
(b) F. W. Patureau and F. Glorius, Angew. Chem., Int. Ed.,
2011, 50, 1977.
Notes and references
1 For general reviews, see: (a) L. D. Quin and J. Tyrell, Funda-
mentals of Heterocyclic Chemistry: Importance in Nature and
in the Synthesis of Pharmaceuticals, John Wiley & Sons Inc.,
New York, 2010; (b) Comprehensive Heterocyclic Chemistry
III, ed. A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and
R. J. K. Taylor, Pergamon, Oxford, 2008; (c) Comprehensive
Heterocyclic Chemistry II, ed. A. R. Katritzky, E. F. V. Scriven
and C. W. Rees, Pergamon, Oxford, 1996; (d) Comprehensive
Heterocyclic Chemistry, ed. A. R. Katritzky and C. W. Rees,
Pergamon, Oxford, 1984; (e) T. Eicher and S. Hauptmann,
The Chemistry of Heterocycles, Wiley-VCH, Weinheim,
2003.
2 For selected reviews, see: (a) G. L. Thomas and
C. W. Johannes, Curr. Opin. Chem. Biol., 2011, 15, 516;
(b) R. Tohme, N. Darwiche and H. Gali-Muhtasib, Mole-
cules, 2011, 16, 9665; (c) S. Dandapani and 11 For reports on other types of redox-neutral transition-
L. A. Marcaurelle, Curr. Opin. Chem. Biol., 2010, 14, 362;
(d) M. E. Welsch, S. A. Snyder and B. R. Stockwell, Curr.
Opin. Chem. Biol., 2010, 14, 347; (e) J. S. Carey, D. Laffan,
C. Thomson and M. T. Williams, Org. Biomol. Chem., 2006,
4, 2337.
3 For recent reviews on C–H amination, see: (a) J. L. Jeffrey
and R. Sarpong, Chem. Sci., 2013, 4, 4092; (b) R. T. Gephart
III and T. H. Warren, Organometallics, 2012, 31, 7728;
(c) J. L. Roizen, M. E. Harvey and J. Du Bois, Acc. Chem.
metal-catalyzed C–H functionalizations with oximes, see:
(a) N. Guimond, S. I. Gorelsky and K. Fagnou, J. Am. Chem.
Soc., 2011, 133, 6449; (b) P. C. Too, S. Z. Chua, S. H. Wong
and S. Chiba, J. Org. Chem., 2011, 76, 6159; (c) P. C. Too,
T. Noji, Y. J. Lim, X. Li and S. Chiba, Synlett, 2011, 2789;
(d) T. K. Hyster and T. Rovis, Chem. Commun., 2011, 47,
11846; (e) X. Zhang, D. Chen, M. Zhao, J. Zhao, A. Jia and
X. Li, Adv. Synth. Catal., 2011, 353, 719; (f) Y. Tan and
J. F. Hartwig, J. Am. Chem. Soc., 2010, 132, 3676;
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(g) P. C. Too, Y.-F. Wang and S. Chiba, Org. Lett., 2010, 12, 15 (a) M.-H. Larraufie, C. Courillon, C. Ollivier, E. Lacôte,
5688.
M. Malacria and L. Fensterbank, J. Am. Chem. Soc., 2010,
132, 4381; (b) M.-H. Larraufie, C. Ollivier, L. Fensterbank
and M. Malacria, Angew. Chem., Int. Ed., 2010, 49, 2178;
(c) A. Beaume, C. Courillon, E. Derat and M. Malacria,
Chem.–Eur. J., 2008, 14, 1238; (d) A. Servais, M. Azzouz,
D. Lopes, C. Courillon and M. Malacria, Angew. Chem., Int.
Ed., 2007, 46, 576.
12 For reports on Cu-catalyzed redox-neutral transformation
with hydroxylamine derivatives, see: (a) W.-M. Liu,
Z.-H. Liu, W.-W. Cheong, L.-Y. Teo Priscilla, Y. Li and
K. Narasaka, Bull. Korean Chem. Soc., 2010, 31, 563;
(b) M. Noack and R. Göttlich, Chem. Commun., 2002, 536.
13 For
a
report on metal-free intramolecular sp3-C–H
amination with ketoximes by thermal treatment of ket- 16 Y.-F. Wang, F.-L. Zhang and S. Chiba, Org. Lett., 2013, 15,
oximes with acetic anhydride, see: C. G. Savarin, C. Grisé, 2842.
J. A. Murry, R. A. Reamer and D. L. Hughes, Org. Lett., 17 The reactions of oximes 6a–h bearing a non-substituted
2007, 9, 981.
benzoyl group might involve not only ortho-addition but
also ipso-addition pathways for the formation of quinazol-
inones 7a–h.
14 See the ESI† for the optimization of the reaction
conditions.
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