Cu(I)-catalyzed diamination of disubstituted terminal olefins: An approach to potent NK1 antagonist

Article abstract of DOI:10.1021/ol900808z

This paper describes a diamination process using di-tert-butyldiaziridinone as nitrogen source and CuCl as catalyst. A wide variety of disubstituted terminal olefins can be efficiently diaminated in good yields under mild condition. This diamination proce

Full text of DOI:10.1021/ol900808z

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2365-2368
Cu(I)-Catalyzed Diamination of
Disubstituted Terminal Olefins: An
Approach to Potent NK1 Antagonist
Yuehong Wen, Baoguo Zhao, and Yian Shi*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
yian@lamar.colostate.edu
Received April 13, 2009
ABSTRACT
This paper describes a diamination process using di-tert-butyldiaziridinone as nitrogen source and CuCl as catalyst. A wide variety of disubstituted
terminal olefins can be efficiently diaminated in good yields under mild condition. This diamination process was used to synthesize potent
NK1 antagonist Sch 425078.
Diamination of olefins provides an effective approach to
vicinal diamines, which are biologically and chemically
important functional moieties.1 Various metal-mediated2,3
and metal-catalyzed4-6 diaminations have been developed.
Recently, we have reported the Pd(0)- and Cu(I)-catalyzed
regioselective diamination of conjugated dienes and
trienes7-9 as well as the dehydrogenative diamination of
terminal olefins10,11 using di-tert-butyldiaziridinone,13,14 di-
aziridinimine,15 or di-tert-butylthiadiaziridine 1,1-dioxide16
(6) For a recent Pd(II)-catalyzed intermolecular diamination of conju-
gated dienes, see: Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I.
(1) For leading reviews, see: (a) Lucet, D.; Le Gall, T.; Mioskowski,
C. Angew. Chem., Int. Ed. 1998, 37, 2580. (b) Mortensen, M. S.; O’Doherty,
G. A. Chemtracts: Org. Chem. 2005, 18, 555. (c) Kotti, S. R. S. S.;
Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101. (d) de Figueiredo,
R. M. Angew. Chem., Int. Ed. 2009, 48, 1190.
J. Am. Chem. Soc. 2005, 127, 7308.
(7) For Pd(0)-catalyzed intermolecular diamination of conjugated dienes
and trienes using di-tert-butyldiaziridinone, see: (a) Du, H.; Zhao, B.; Shi,
Y. J. Am. Chem. Soc. 2007, 129, 762. (b) Xu, L.; Du, H.; Shi, Y. J. Org.
Chem. 2007, 72, 7038. (c) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am.
(2) For examples of metal-mediated diaminations, see the following.
Tl: (a) Aranda, V. G.; Barluenga, J.; Aznar, F. Synthesis 1974, 504. Os: (b)
Chong, A. O.; Oshima, K.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99,
3420. (c) Mun˜iz, K. Eur. J. Org. Chem. 2004, 2243. Pd: (d) Ba¨ckvall, J.-E.
Tetrahedron Lett. 1978, 163. Hg: (e) Barluenga, J.; Alonso-Cires, L.;
Asensio, G. Synthesis 1979, 962. Co: (f) Becker, P. N.; White, M. A.;
Bergman, R. G. J. Am. Chem. Soc. 1980, 102, 5676. Mn: (g) Fristad, W. E.;
Brandvold, T. A.; Peterson, J. R.; Thompson, S. R. J. Org. Chem. 1985,
Chem. Soc. 2007, 129, 11688.
(8) For Cu(I)-catalyzed intermolecular diamination of conjugated dienes
and trienes using di-tert-butyldiaziridinone, see: (a) Yuan, W.; Du, H.; Zhao,
B.; Shi, Y. Org. Lett. 2007, 9, 2589. (b) Du, H.; Zhao, B.; Yuan, W.; Shi,
Y. Org. Lett. 2008, 10, 4231
(9) For Cu(I)-catalyzed intermolecular diamination of conjugated dienes,
trienes, and activated terminal olefins using diaziridinimine, see: Zhao, B.;
.
Du, H.; Shi, Y. Org. Lett. 2008, 10, 1087
.
50, 3647
.
(10) For Pd(0)-catalyzed intermolecular allylic and homoallylic C-H
diamination of terminal olefins using di-tert-butyldiaziridinone, see: (a) Du,
H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496. (b)
(3) For a recent Cu(II)-mediated intramolecular diamination, see: (a)
Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem. Soc. 2005, 127,
11250. (b) Zabawa, T. P.; Chemler, S. R. Org. Lett. 2007, 9, 2035
.
Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 8590.
(4) For recent Pd(II)- and Ni(II)-catalyzed intramolecular diamination
of olefins, see: (a) Streuff, J.; Ho¨velmann, C. H.; Nieger, M.; Mun˜iz, K.
J. Am. Chem. Soc. 2005, 127, 14586. (b) Mun˜iz, K.; Streuff, J.; Ho¨velmann,
C. H.; Nu´n˜ez, A. Angew. Chem., Int. Ed. 2007, 46, 7125. (c) Mun˜iz, K.
J. Am. Chem. Soc. 2007, 129, 14542. (d) Mun˜iz, K.; Ho¨velmann, C. H.;
Streuff, J. J. Am. Chem. Soc. 2008, 130, 763. (e) Sibbald, P. A.; Michael,
(11) For Pd(0)-catalyzed dehydrogenative diamination of terminal olefins
using di-tert-butylthiadiaziridine 1,1-dioxide, see: Wang, B.; Du, H.; Shi,
Y. Angew. Chem., Int. Ed. 2008, 47, 8224
(12) For Cu(I)-catalyzed intermolecular diamination of activated terminal
.
olefins using di-tert-butylthiadiaziridine 1,1-dioxide, see: Zhao, B.; Yuan,
W.; Du, H.; Shi, Y. Org. Lett. 2007, 9, 4943
.
F. E. Org. Lett. 2009, 11, 1147
.
(13) Greene, F. D.; Stowell, J. C.; Bergmark, W. R. J. Org. Chem. 1969,
(5) For Rh(II)- and Fe(III)-catalyzed diamination with TsNCl2, see: (a)
Li, G.; Wei, H.-X.; Kim, S. H.; Carducci, M. D. Angew. Chem., Int. Ed.
2001, 40, 4277. (b) Wei, H.-X.; Kim, S. H.; Li, G. J. Org. Chem. 2002, 67,
34, 2254
.
(14) For a leading review on diaziridinones, see: Heine, H. W. In The
Chemistry of Heterocyclic Compounds; Hassner, A., Ed.; John Wiley &
4777
.
Sons, Inc.: Hoboken, NJ, 1983; p 547.
10.1021/ol900808z CCC: $40.75
Published on Web 05/01/2009
 2009 American Chemical Society

as the nitrogen sources. The Cu(I)-catalyzed diamination
process has also been extended to activated monosubstituted
terminal olefins such as styrenes, enynes, enol ether, etc.9,12
Considering the fact that 4,4-disubstituted 2-imidazolidinones
(Figure 1) have been shown to be potent NK1 antagonists,17
Table 1. Catalytic Diamination of Disubstituted Terminal
Olefinsa
Figure 1. NK1 antagonists.
and in conjunction with our efforts to expand the diamination
scope, we have investigated the diamination of disubstituted
simple terminal olefins using di-tert-butyldiaziridinone (2)
as the nitrogen source (Scheme 1).8 Herein, we wish to report
our studies on this subject.
Scheme 1
Initial studies were carried out using 2-phenylpropene as
the substrate and di-tert-butyldiaziridinone (2) as the nitrogen
source. When Pd(PPh3)4 was used as catalyst, only a trace
amount of diamination product was observed. However,
>95% conversion was obtained when the reaction was carried
out with 5 mol % of CuCl-PPh3 (1:1) in CDCl3 at 65 °C.18
As shown in Table 1, various 2-phenylpropenes with different
substituents on the phenyl ring can be successfully diami-
a All reactions were carried out with olefin (1) (0.4 mmol), di-tert-
butyldiaziridinone (2) (0.8 mmol) (added by syringe pump over 8 h), and
CuCl-PPh3 (1:1) (0.02 mmol) in CDCl3 (0.3 mL) at 65 °C unless otherwise
stated. Upon complete addition of 2, the reaction mixture was stirred at 65
°C for an additional time period (1 h for entries 1, 4, 5, 6, 8, and 9; 2 h for
entries 7, 10, and 15; 4 h for entry 11; 7 h for entries 3, 12, 14, and 16;
10 h for entries 2 and 13). b CuCl-PPh3 (1:1) (0.04 mmol) was used. c The
reaction was carried out with olefin (0.2 mmol), di-tert-butyldiaziridinone
(2) (0.4 mmol), and CuCl-PPh3 (1:1) (0.02 mmol) in CDCl3 (0.3 mL).
d Isolated yield based on olefin.
(15) (a) Quast, H.; Schmitt, E. Angew. Chem., Int. Ed. 1969, 8, 448. (b)
L’abbe´, G.; Verbruggen, A.; Minami, T.; Toppet, S. J. Org. Chem. 1981,
46, 4478. (c) Mestres, R.; Palomo, C. Synthesis 1980, 755.
nated in moderate to good yield (Table 1, entries 1-9).19
2-Isopropenylnaphthalene 1j is also an effective substrate
(Table 1, entry 10). Substrates with different alkyl substit-
uents (such as ethyl, benzyl, and methoxymethyl groups) can
also be diaminated in 55-71% yield (Table 1, entries
11-14). The diamination process can also be extended to
R,ꢀ-unsaturated esters (Table 1, entries 15 and 16). However,
(16) Timberlake, J. W.; Alender, J.; Garner, A. W.; Hodges, M. L.;
¨
Ozmeral, C.; Szilagyi, S.; Jacobus, J. O. J. Org. Chem. 1981, 46, 2082.
(17) For leading references, see: (a) Reichard, G. A.; Stengone, C.;
Paliwal, S.; Mergelsberg, I.; Majmundar, S.; Wang, C.; Tiberi, R.; McPhail,
A. T.; Piwinski, J. J.; Shih, N.-Y. Org. Lett. 2003, 23, 4249. (b) Shue,
H.-J.; Chen, X.; Shih, N.-Y.; Blythin, D. J.; Paliwal, S.; Lin, L.; Gu, D.;
Schwerdt, J. H.; Shah, S.; Reichard, G. A.; Piwinski, J. J.; Duffy, R. A.;
Lachowicz, J. E.; Coffin, V. L.; Liu, F.; Nomeir, A. A.; Morgan, C. A.;
Varty, G. B. Bioorg. Med. Chem. Lett. 2005, 15, 3896. (c) Shue, H.-J.;
Chen, X.; Schwerdt, J. H.; Paliwal, S.; Blythin, D. J.; Lin, L.; Gu, D.; Wang,
C.; Reichard, G. A.; Wang, H.; Piwinski, J. J.; Duffy, R. A.; Lachowicz,
J. E.; Coffin, V. L.; Nomeir, A. A.; Morgan, C. A.; Varty, G. B.; Shih,
N.-Y. Bioorg. Med. Chem. Lett. 2006, 16, 1065.
(19) Representative diamination procedure (Table 1, entry 1): To a
1.5 mL vial equipped with a stir bar were added CuCl (0.002 g, 0.02 mmol),
triphenylphosphine (0.0052 g, 0.02 mmol), and CDCl3 (0.3 mL). After the
mixture was stirred at room temperature for 10 min, 2-phenylpropene (1a)
(0.047 g, 0.4 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, 0.8 mmol) was added by syringe pump over 8 h. The reaction mixture
was stirred at this temperature for an additional 1 h and purified by flash
chromatography (silica gel, hexane/ether ) 10/1) to give diamination product
3a as a white solid (0.105 g, 91%).
(18) When the CuCl-catalyzed diamination of 2-phenylpropene was
carried out with di-tert-butylthiadiaziridine 1,1-dioxide or 1,2-di-tert-butyl-
3-(cyanimino)diaziridine as the nitrogen source under the previously reported
conditions (refs 9 and 12), only a small amount of diamination product or
a messy mixtutre was obtained, respectively.
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Org. Lett., Vol. 11, No. 11, 2009

dialkyl terminal olefins, such as 2-methyl-3-phenyl-1-pro-
pene, are not effective substrates for this diamination.
The deprotection of the diamination products was inves-
tigated with compound 3a (Scheme 2). Treating 3a with
Scheme 3
Scheme 2
CH3SO3H in hexane (1:10, v/v) at room temperature gave
monodeprotected compound 4a in 99% yield.20 The structure
of compound 4a was confirmed by NOE analysis and the X-
ray structure of related compound 14 (Figure 2, Scheme 4).
dazolidinone Sch 42507817 is outlined in Scheme 3. Disub-
stituted terminal olefin 9 was readily prepared in 77% yield
by reaction between R-bromomethylstyrene (7) and com-
mercially available (R)-1-(3,5-bis(trifluoromethyl)phenyl)e-
thanol using NaH as base. Diamination of olefin 9 with
CuCl-P(OPh)3 and di-tert-butyldiaziridinone (2) gave 4,4-
disubstituted 2-imidazolidinones 10 and 11 in 35% and 30%
yield, respectively,21 after flash chromatography (the less
polar spot on the TLC corresponds to compound 10).
Removal of both tert-butyl groups of compound 10 provided
compound 12 (Sch 425078) in 74% yield.
Scheme 4
Figure 2. X-ray structure of compound 14.
When the deprotection was carried out at 65 °C, both tert-
butyl groups were smoothly removed in 85% yield. Free
diamine 6a can be obtained in 87% yield directly from 3a
by deprotection with concentrated HCl.7c,10
The application of this catalytic diamination to the
synthesis of potent NK1 antagonist 4,4-disubstituted 2-imi-
(20) Zhao, B.; Du, H.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 7220.
(21) Diamination of olefin 9 with CuCl-PPh3 (1:1) (10 mol %) in CDCl3
at 65 °C for 10 h gave compound 10 in 30% yield and 11 in 33% yield.
Diamination of 9 with CuCl-(R)-DTBM-SEGPHOS (2:1) (10 mol %)8
in CDCl3 at 65 °C for 10 h gave compound 10 in 32% yield and 11 in 29%
yield.
Org. Lett., Vol. 11, No. 11, 2009
2367

To further confirm the configuration of the diamination
product 10, one tert-butyl group was selectively removed
using CF3CO2H at room temperature to give compound 13,
which was converted to compound 14 with n-BuLi and
benzoyl chloride22 (Scheme 4). The structure of compound
14 was determined by X-ray analysis (Figure 2). The
determination of the structure of monodeprotected product
13 supports the structure assignment of monodeprotected
compound 4a in Scheme 2.
In summary, a variety of disubstituted terminal olefins have
been effectively diaminated using CuCl as catalyst and di-
tert-butyldiaziridinone as nitrogen source, which provides a
rapid access to various 4,4-disubstituted 2-imidazolidino-
nes.23 In addition, the synthesis of 4,4-disubstituted 2-imi-
dazolidinone Sch 425078 (potent NK1 antagonist) has been
achieved in three steps using this diamination. The ability
to selectively remove one or two protecting groups would
provide opportunities to introduce different substituents on
the nitrogens if desired. Future efforts will be devoted to
the development of an asymmetric diamination process and
its applications.
(22) Rahimizadeh, M.; Kam, K.; Jenkins, S. I.; McDonald, R. S.;
Harrison, P. H. M. Can. J. Chem. 2002, 80, 517.
(23) For recent leading references on other approaches to 4,4-disubsti-
tuted-2-imidazolidinones, see: (a) Trost, B. M.; Fandrick, D. R. J. Am. Chem.
Soc. 2003, 125, 11836. (b) Mehrotra, M. M.; Heath, J. A.; Smyth, M. S.;
Pandey, A.; Rose, J. W.; Seroogy, J. M.; Volkots, D. L.; Nannizzi-Alaimo,
L.; Park, G. L.; Lambing, J. L.; Hollenbach, S. J.; Scarborough, R. M.
J. Med. Chem. 2004, 47, 2037. (c) Shen, D.; Zhang, F.; Brady, E. J.;
Candelore, M. R.; Dallas-Yang, Q.; Ding, V. D.-H.; Dragovic, J.; Feeney,
W. P.; Jiang, G.; McCann, P. E.; Mock, S.; Qureshi, S. A.; Saperstein, R.;
Shen, X.; Tamvakopoulos, C.; Tong, X. C.; Tota, L. M.; Wright, M. J.;
Yang, X.; Zheng, S.; Chapman, K. T.; Zhang, B.; Tata, J. R.; Parmee, E. R.
Bioorg. Med. Chem. Lett. 2005, 15, 4564. (d) Brackmann, F.; Es-Sayed,
M.; de Meijere, A. Eur. J. Org. Chem. 2005, 2250. (e) Nadir, U. K.; Krishna,
R. V.; Singh, A. Tetrahedron Lett. 2005, 46, 479. (f) Reference 6. (g)
Reference 4a. (h) Fritz, J. A.; Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2006,
8, 2531. (i) Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett.
2006, 8, 1073. (j) Lanter, J. C.; Fiordeliso, J. J.; Allan, G. F.; Musto, A.;
Hahn, D. W.; Sui, Z. Bioorg. Med. Chem. Lett. 2006, 16, 5646. (k) Reference
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Acknowledgment. We are grateful for the generous
financial support from the General Medical Sciences of the
National Institutes of Health (GM083944-02).
Supporting Information Available: Experimental pro-
cedures, characterization of diamination products 3, NOE
1
studies of compound 4a, and H and 13C NMR spectra of
compounds 3, 4a, 5a, 6a, and 9-14 along with the X-ray
data of compound 14. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL900808Z
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