Cu(I)-catalyzed C-H α-amination of aryl ketones: Direct synthesis of imidazolinones

Article abstract of DOI:10.1021/jo9004553

(Chemical Equation Presented) This paper describes an α-amination process of aryl ketones using CuCl as catalyst and di-tert-butyldiaziridinone as the nitrogen source. A variety of imidazolinone derivatives are prepared in moderate yields under mild condi

Full text of DOI:10.1021/jo9004553

SCHEME 1. r-Amination of Ester and Ketone
Cu(I)-Catalyzed C-H r-Amination of Aryl
Ketones: Direct Synthesis of Imidazolinones
Baoguo Zhao, Haifeng Du, and Yian Shi*
Department of Chemistry, Colorado State UniVersity, Fort
Collins, Colorado 80523
yian@lamar.colostate.edu
ReceiVed February 27, 2009
hydantoins (3) with di-tert-butyldiaziridinone (2)4-7 and CuCl
(Scheme 1).8 In further investigation on C-H amination with
di-tert-butyldiaziridinone (2), we have found that aryl ketone 4
can also be aminated at the R position to form imidazolinone 5
directly using CuCl as catalyst (Scheme 1). Imidazolinones are
important moieties that are present in various biologically active
compounds,9 such as MurB inhibitor9b and CGRP receptor
antagonist9d (Figure 1). In general, imidazolinones can be prepared
by cyclization of R-amino derivatives of ketones, aldehydes, and
related compounds,9,10 or by derivatization of imidazolinones.11
The current direct R-amination of ketones provides a valuable
This paper describes an R-amination process of aryl ketones
using CuCl as catalyst and di-tert-butyldiaziridinone as the
nitrogen source. A variety of imidazolinone derivatives are
prepared in moderate yields under mild conditions. A
possible catalytic cycle is proposed for this reaction.
(4) For leading references on Pd(0) and Cu(I)-catalyzed diamination of olefins
with di-tert-butyldiaziridinone, see: (a) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem.
Soc. 2007, 129, 762. (b) Du, H.; Yuan, W.; Zhao, B; Shi, Y J. Am. Chem. Soc.
2007, 129, 7496. (c) Yuan, W.; Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9,
2589. (d) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129,
11688. (e) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 8590. (f) Du,
H.; Zhao, B.; Yuan, W.; Shi, Y. Org. Lett. 2008, 10, 4231.
(5) For a leading review on diaziridinones, see, Heine, H. W. In The
Chemistry of Heterocyclic Compounds; Hassner, A., Ed.; John Wiley & Sons,
Inc: New York, 1983; p 547.
(6) Greene, F. D.; Stowell, J. C.; Bergmark, W. R. J. Org. Chem. 1969, 34,
2254.
(7) For leading references on the reaction of diaziridines with ketenes, see:
(a) Shevtsov, A. V.; Petukhova, V. Yu.; Strelenko, Yu. A.; Lyssenko, K. A.;
Makhova, N. N.; Tartakovsky, V. A. Russ. Chem. Bull., Int. Ed. 2005, 54, 1021.
(b) Shevtsov, A. V.; Ananikov, V. P.; Makhova, N. N. Russ. J. Org. Chem 2007,
43, 1101.
Amines and their derivatives are very important functional
moieties contained in many natural products, pharmaceutical
agents, and chemical materials. A variety of efficient methods
have been developed to introduce nitrogens.1 The formation of
C-N bonds by direct C-H amination is highly attractive, and
great progress has been achieved in this area.2,3 In our studies
on amination with diaziridinones, recently we have found that
esters (1) can be directly aminated at the R position to form
(1) For recent leading reviews, see: (a) Osborn, H. M. I.; Sweeney, J.
Tetrahedron: Asymmetry 1997, 8, 1693. (b) Lucet, D.; Le Gall, T.; Mioskowski,
C. Angew. Chem., Int. Ed. 1998, 37, 2580. (c) Wolfe, J. P.; Wagaw, S.; Marcoux,
J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (d) Hartwig, J. F. Acc.
Chem. Res. 1998, 31, 852. (e) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400. (f) Hultzsch, K. C. AdV. Synth. Catal. 2005, 347, 367. (g)
Muzart, J. Tetrahedron 2005, 61, 4179. (h) Kotti, S. R. S. S.; Timmons, C.; Li,
G. Chem. Biol. Drug. Des. 2006, 67, 101. (i) Wolfe, J. P. Eur. J. Org. Chem.
2007, 571. (j) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. ReV. 2007,
107, 2080. (k) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S.
Chem. ReV. 2007, 107, 5318.
(2) For leading reviews, see: (a) Davies, H. M. L.; Long, M. S. Angew. Chem.,
Int. Ed 2005, 44, 3518. (b) Espino, C. G.; Du Bois, J. In Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; WILEY-VCH: Weinheim,
Germany, 2005; Chapter 17. (c) Dick, A. R.; Sanford, M. S. Tetrahedron 2006,
62, 2439.
(8) Zhao, B.; Du, H.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 7220.
(9) For leading references, see: (a) Carling, R. W.; Moore, K. W.; Moyes,
C. R.; Jones, E. A.; Bonner, K.; Emms, F.; Marwood, R.; Patel, S.; Patel, S.;
Fletcher, A. E.; Beer, M.; Sohal, B.; Pike, A.; Leeson, P. D. J. Med. Chem.
1999, 42, 2706. (b) Bronson, J. J.; DenBleyker, K. L.; Falk, P. L.; Mate, R. A.;
Ho, H.-T.; Pucci, M. J.; Snyder, L. B. Bioorg. Med. Chem. Lett. 2003, 13, 873.
(c) Burgey, C. S.; Stump, C. A.; Nguyen, D. N.; Deng, J. Z.; Quigley, A. G.;
Norton, B. R.; Bell, I. M.; Mosser, S. D.; Salvatore, C. A.; Rutledge, R. Z.;
Kane, S. A.; Koblan, K. S.; Vacca, J. P.; Graham, S. L.; Williams, T. M. Biorg.
Med. Chem. Lett. 2006, 16, 5052. (d) Shaw, A. W.; Paone, D. V.; Nguyen, D. N.;
Stump, C. A.; Burgey, C. S.; Mosser, S. D.; Salvatore, C. A.; Rutledge, R. Z.;
Kane, S. A.; Koblan, K. S.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Bioorg.
Med. Chem. Lett. 2007, 17, 4795. (e) Congiu, C.; Cocco, M. T.; Onnis, V. Bioorg.
Med. Chem. Lett. 2008, 18, 989. (f) Watanabe, K.; Morinaka, Y.; Hayashi, Y.;
Shinoda, M.; Nishi, H.; Fukushima, N.; Watanabe, T.; Ishibashi, A.; Yuki, S.;
Tanaka, M. Bioorg. Med. Chem. Lett. 2008, 18, 1478. (g) Xue, N.; Yang, X.;
Wu, R.; Chen, J.; He, Q.; Yang, B.; Lu, X.; Hu, Y. Bioorg. Med. Chem. 2008,
16, 2550.
(10) For leading references, see: (a) Chawla, H. M.; Pathak, M. Tetrahedron
1990, 46, 1331. (b) Markwalder, J. A.; Pottorf, R. S.; Seitz, S. P. Synlett 1997,
521. (c) Akester, J.; Cui, J.; Fraenkel, G. J. Org. Chem. 1997, 62, 431. (d)
Wendeborn, S.; Winkler, T.; Foisy, I. Tetrahedron Lett. 2000, 41, 6387. (e) Fevig,
J. M.; Pinto, D. J.; Han, Q.; Quan, M. L.; Pruitt, J. R.; Jacobson, I. C.; Galemmo,
R. A., Jr.; Wang, S.; Orwat, M. J.; Bostrom, L. L.; Knabb, R. M.; Wong, P. C.;
Lam, P. Y. S.; Wexler, R. R. Bioorg. Med. Chem. Lett. 2001, 11, 641. (f) Sosa,
A. C. B.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 2002, 67, 4498. (g) Lee,
S.-H.; Yoshida, K.; Matsushita, H.; Clapham, B.; Koch, G.; Zimmermann, J.;
Janda, K. D. J. Org. Chem. 2004, 69, 8829. (h) Parcher, B. W.; Erion, D. M.;
Dang, Q. Tetrahedron Lett. 2004, 45, 2677. (i) Siamaki, A. R.; Black, D. A.;
Arndtsen, B. A. J. Org. Chem. 2008, 73, 1135.
(3) For recent leading references on sp3 C-H amination, see: (a) Espino, C. G.;
Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935. (b)
Leung, S. K.-Y.; Huang, J.-S.; Liang, J.-L.; Che, C.-M.; Zhou, Z.-Y. Angew.
Chem., Int. Ed. 2003, 42, 340. (c) D´ıaz-Requejo, M. M.; Belderra´ın, T. R.;
Nicasio, M. C.; Trofimenko, S.; Pe´rez, P. J. J. Am. Chem. Soc. 2003, 125, 12078.
(d) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127, 14198. (e)
Liang, C.; Robert-Peillard, F.; Fruit, C.; Mu¨ller, P.; Dodd, R. H.; Dauban, P.
Angew. Chem., Int. Ed. 2006, 45, 4641. (f) Fiori, K. W.; Du Bois, J. J. Am.
Chem. Soc. 2007, 129, 562. (g) Lebel, H.; Huard, K. Org. Lett. 2007, 9, 639.
(h) Li, Z.; Capretto, D. A.; Rahaman, R.; He, C. Angew. Chem., Int. Ed. 2007,
46, 5184. (i) Liang, C.; Collet, F.; Robert-Peillard, F.; Mu¨ller, P.; Dodd, R. H.;
Dauban, P. J. Am. Chem. Soc. 2008, 130, 343. (j) Hasegawa, Y.; Watanabe, M.;
Gridnev, I. D.; Ikariya, T. J. Am. Chem. Soc. 2008, 130, 2158. (k) Reed, S. A.;
White, M. C. J. Am. Chem. Soc. 2008, 130, 3316.
10.1021/jo9004553 CCC: $40.75
Published on Web 04/29/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4411–4413 4411

TABLE 1. Cu(I)-Catalyzed r-Amination of Ketonesa
FIGURE 1. Biologically active compounds containing imidazolinones.
alternative method for the synthesis of imidazolinones. Herein we
wish to report our studies on this subject.
When acetophenone 4a was initially treated with di-tert-
butyldiaziridinone (2) and 5 mol % of CuCl-P(n-Bu)3 (1:1) in
CDCl3 at 65 °C in an NMR tube for 12 h, imidazolinone 5a
was formed in 39% yield. The yield can be improved to 46%
using 5 mol % of CuCl-P(n-Bu)3 (1:2) in dry 1,2-dichloroethane
and by slow addition of di-tert-butyldiaziridinone over 8 h
(Table 1, entry 1). As shown in Table 1, various substituted
acetophenones were successfully R-aminated to give the cor-
responding imidazolinone derivatives in moderate yields (Table
1, entries 2-7) (the X-ray structure of 5b is shown in Supporting
Information). The substituent on the aryl ring appears to have
little influence on the reaction. Methyl 2-naphthyl ketone and
methyl 2-thienyl ketone were also effective substrates that
yielded the corresponding R-amination products with moderate
yields (Table 1, entries 8 and 9). Butyrophenone was also
R-aminated to afford the imidazolinone albeit in low yield (Table
1, entry 10). In all these cases, the relatively low yields obtained
are largely due to relatively low conversions of ketone substrates.
When the reaction was carried out at a larger scale (4.0 mmol),
slightly lower yields were obtained (Table 1, entries 1 and 8).
The aryl group of the ketone substrate appears to be important,
and R,ꢀ-unsaturated ketones such as (E)-4-phenylbut-3-en-2-
one and dialkyl ketones such as octan-2-one are not effective
substrates under the current reaction conditions. The deprotection
of the resulting imidazolinone product was also investigated with
compound 5a. Treating 5a with CF3CO2H at 65 °C for 5 h led
to a selective removal of one tert-butyl group to give compound
6 in 97% yield (Scheme 2).4a,d,8 The structure of 6 was
confirmed by the X-ray analysis (see Supporting Information).
However, removal of two tert-butyl groups under more forcing
conditions led to a mixture of unidentified products. More
effective deprotection procedures need to be further developed.
While an exact reaction mechanism awaits further study, a
plausible catalytic cycle similar to the formation of hydantoin
is proposed in Scheme 3.8 The N-N bond of di-tert-butyldiaz-
iridinone (2) is probably reduced initially by CuCl to form
species 74c,12-15 or 7a, which then abstracts a hydrogen or
a All reactions were carried out with ketone (0.4 mmol),
1,2-di-tert-butyldiaziridinone (2) (0.80 mmol) (added slowly over 8 h
with syringe pump), CuCl-P(n-Bu)3 (1:2) (0.02 mmol) in DCE (0.1 mL)
at 65 °C under argon for 12 h unless otherwise stated. For entries 6 and
9, 60 °C was used. b Isolated yield based on ketone. c Reaction was
carried out with 4 mmol of the ketone.
(11) For leading references, see: (a) Wamhoff, H.; Kleimann, W.; Kunz, G.;
Theis, C. H. Angew. Chem. 1981, 93, 601. (b) Lu, J.; Tan, X.; Chen, C. J. Am.
Chem. Soc. 2007, 129, 7768. (c) Sheppeck, J. E., II; Gilmore, J. L.; Tebben, A.;
Xue, C.-B.; Liu, R.-Q.; Decicco, C. P.; Duan, J. J.-W. Bioorg. Med. Chem. Lett.
2007, 17, 2769.
(12) For a leading review on metal-promoted radical reactions, see: Iqbal,
J.; Bhatia, B.; Nayyar, N. K. Chem. ReV. 1994, 94, 519.
(13) For leading reviews on CuX-catalyzed atom transfer reactions, see: (a)
Patten, T. E.; Matyjaszewski, K. Acc. Chem. Res. 1999, 32, 895. (b) Clark, A. J.
Chem. Soc. ReV. 2002, 31, 1.
(14) For leading references on nitrogen-centered radicals, see: (a) Stella, L.
In Radicals in Organic Synthesis; Renaud, P.; Sibi, M. P., Ed.; Wiley-VCH:
Weinheim, Germany, 2001; Vol. 2, p 407. (b) Guin, J.; Mu¨ck-Lichtenfeld, C.;
Grimme, S.; Studer, A. J. Am. Chem. Soc. 2007, 129, 4498.
proton from ketone 4 to form 8. Species 8 undergoes a reductive
elimination to give compound 9 and regenerate CuCl catalyst.16,17
Imidazolinone 5 is formed by cyclization of compound 9 and
loss of water under the reaction conditions.
4412 J. Org. Chem. Vol. 74, No. 11, 2009

SCHEME 2. Selective Deprotection of Imidazolinone 5a
added by syringe pump over 8 h. The reaction mixture was stirred
at this temperature for an additional 4 h and purified by flash
chromatography (silica gel, petroleum ether:ethyl ether ) 5:1) to
give imidazolinone 5a as a white solid (0.050 g, 46%). mp.
128-129 °C; IR (film) 1669 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.31 (s, 5H), 6.05 (s, 1H), 1.54 (s, 9H), 1.42 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 153.7, 134.9, 130.5, 127.88, 127.85, 122.8, 108.2,
58.3, 54.7, 30.4, 28.3; HRMS Calcd for C17H24N2O (M+): 272.1889.
Found: 272.1890.
SCHEME 3. Proposed Catalytic Cycle for the r-Amination
Representative r-Amination Procedure on 4.0 mmol Scale
(Table 1, entry 8). To a 10 mL round-bottomed flask equipped
with a stir bar was added CuCl (0.020 g, 0.20 mmol) and methyl
2-naphthyl ketone (4h) (0.68 g, 4.0 mmol). The sealed flask was
evacuated and filled with Ar three times, followed by addition of
1,2-dichloroethane (1.0 mL) and tri-n-butylphosphine (0.10 mL,
0.40 mmol). After stirring at room temperature for 10 min, the
reaction mixture was warmed to 65 °C using an oil bath, and then
di-tert-butyldiaziridinone (2) (1.36 g, 8.0 mmol) was added by
syringe pump over 8 h. The reaction mixture was stirred at this
temperature for an additional 4 h and purified by flash chromatog-
raphy (silica gel, petroleum ether:ethyl ether ) 5:1) to give
unreacted methyl 2-naphthyl ketone (4h) (0.22 g) and imidazolinone
5h (0.455 g, 49%) as a white solid. mp. 117-118 °C; IR (film)
In summary, a variety of aryl ketones can be successfully
R-aminated to directly form imidazolinones in moderate yields
using CuCl as catalyst and di-tert-butyldiaziridinone (2) as
nitrogen source under mild reaction conditions. The current
R-amination process can be potentially useful for the synthesis
of biologically active imidazolinone derivatives.
1
1677 cm-1; H NMR (300 MHz, CDCl3) δ 7.86-7.76 (m, 4H),
7.52-7.42 (m, 3H), 6.13 (s, 1H), 1.57 (s, 9H), 1.46 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 153.9, 133.1, 132.8, 132.4, 129.0, 128.3,
128.0, 127.8, 127.1, 126.6, 126.4, 122.9, 108.8, 58.5, 54.8, 30.4,
28.3; HRMS Calcd for C21H26N2O (M+): 322.2045. Found:
322.2044.
Deprotection of 5a (Scheme 2). A mixture of 5a (0.30 g, 1.1
mmol) and CF3CO2H (3.0 mL) was stirred at 65 °C under argon
atmosphere for 5 h, concentrated, and purified by flash chroma-
tography (silica gel, diethyl ether) to give compound 6 as a white
Experimental Section
Representative r-Amination Procedure on 0.4 mmol Scale
(Table 1, entry 1). To a 1.5 mL vial equipped with a stir bar was
added CuCl (0.002 g, 0.02 mmol). The sealed vial was evacuated
and filled with Ar three times, followed by addition of 1,2-
dichloroethane (0.10 mL) and tri-n-butylphosphine (0.01 mL, 0.04
mmol). After the mixture was stirred at room temperature for 10
min, acetophenone (4a) (0.048 g, 0.40 mmol) was added. The
reaction mixture was warmed to 65 °C using an oil bath with
stirring, and di-tert-butyldiaziridinone (2) (0.136 g, 0.80 mmol) was
solid (0.23 g, 97%). mp. 170-171 °C; IR (film) 3151, 1676 cm-1
;
1H NMR (300 MHz, CDCl3) δ 11.90 (s, 1H), 7.54 (d, J ) 7.8 Hz,
2H), 7.35 (dd, J ) 7.8, 7.2 Hz, 2H), 7.21 (t, J ) 7.2 Hz, 1H), 6.65
(d, J ) 2.7 Hz, 1H), 1.64 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
155.0, 129.9, 128.9, 126.6, 123.2, 121.7, 105.0, 55.0, 28.5; HRMS
Calcd for C13H16N2O (M+): 216.1263. Found: 216.1265.
Acknowledgment. We are grateful to the generous financial
support from the General Medical Sciences of the National
Institutes of Health (GM083944-02).
(15) For leading references on Cu(I)-catalyzed homolytic cleavage of N-O
bonds of oxaziridines, see: (a) Aube´, J.; Peng, X.; Wang, Y.; Takusagawa, F.
J. Am. Chem. Soc. 1992, 114, 5466. (b) Aube´, J. Chem. Soc. ReV 1997, 26, 269.
(c) Black, D. StC.; Edwards, G. L.; Laaman, S. M. Tetrahedron Lett. 1998, 39,
5853. (d) Black, D. StC.; Edwards, G. L.; Laaman, S. M. Synthesis 2006, 1981.
(16) For leading references on Cu(II)-mediated oxidative coupling reactions,
see: (a) Schmittel, M.; Haeuseler, A. J. Organomet. Chem. 2002, 661, 169. (b)
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450. (c) Richter,
J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.; Castroviejo, M. P.; Baran,
P. S. J. Am. Chem. Soc. 2007, 129, 12857.
Supporting Information Available: The spectroscopic and
analytic data of compounds 5b-g, i, j, the X-ray data of
1
compounds 5b and 6 along with the H and 13C NMR spectra
of imidazolinone products 5 and 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) For a leading review on organocopper reagents, see: Lipshutz, B. H.;
Sengupta, S. Org. React. 1992, 41, 135.
JO9004553
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