Gold(1)-catalyzed intramolecular dihydroamination of allenes with N,N′-disubstituted ureas to form bicyclic imidazolidin-2-ones

Article abstract of DOI:10.1021/ol900730w

Reaction of W-δ-allenyl urea 1 with a catalytic 1:1 mixture of gold(1) N-heterocyclic carbene complex (5)AuCI [5 = 1,3-bis(2,6- diisopropylphenyl)imidazol-2-ylidine] and AgPF₆ at room temperature for 2 h led to isolation of bicyclic imidazolidi

Full text of DOI:10.1021/ol900730w

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2671-2674
Gold(I)-Catalyzed Intramolecular
Dihydroamination of Allenes with
N,N′-Disubstituted Ureas To Form
Bicyclic Imidazolidin-2-ones
Hao Li and Ross A. Widenhoefer*
Duke UniVersity, Department of Chemistry, French Family Science Center,
Durham, North Carolina 27708-0346
rwidenho@chem.duke.edu
Received April 6, 2009
ABSTRACT
Reaction of N-δ-allenyl urea 1 with a catalytic 1:1 mixture of gold(I) N-heterocyclic carbene complex (5)AuCl [5 ) 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidine] and AgPF6 at room temperature for 2 h led to isolation of bicyclic imidazolidin-2-one 4 in 93% yield with
g98% diastereomeric purity. Gold-catalyzed dihydroamination was effective for a number of N-δ- and N-γ-allenyl ureas to form the corresponding
bicyclic imidazolidin-2-ones in good yield with high diastereoselectivity.
Vicinal diamines and related carboxamide derivatives such
as imidazolidin-2-ones are components of a number of
naturally occurring and biologically active molecules and
find application as chiral ligands and auxiliaries.1,2 The
direct diamination of an alkene represents a particularly
attractive approach to the synthesis of vicinal diamines.3,4
Recent efforts in this area have led to the development of
effective processes for the uncatalyzed5,6 or Pd(II)-7,8 or
Ni(II)-catalyzed9 oxidative diamination of alkenes with HN-
R-NH functionality and for the Pd(0)-10 or Cu(I)-catalyzed11
diamination of alkenes with di-tert-butyldiaziridinone and
related reagents. In this context, we considered the catalytic
dihydroamination of allenes as a redox-neutral and atom-
economic alternative to alkene diamination for the synthesis
of vicinial diamine derivatives. Such an approach would
obviate the need for a stoichiometric oxidant or specialized
diaziridine reagent and would present new opportunities for
stereoselective synthesis. Here, we describe the gold(I)-
catalyzed, diastereoselective intramolecular dihydroamination
of allenes with N,N’-disubstituted ureas to form polycyclic
imidazolidin-2-ones.
(2) For examples of biologically active imidazolidin-2-ones, see: (a) Li,
J.; Sutton, J.; Nirschl, A.; Zou, Y.; Wang, H.; Sun, C.; Pi, Z.; Johnson, R.;
Krystek, S.; Seethala, R.; Golla, R.; Sleph, P.; Beehler, B.; Grover, G.;
Fura, A.; Vyas, V.; Li, C.; Gougoutas, J.; Galella, M.; Zahler, R.; Ostrowski,
J.; Hamann, L. J. Med. Chem. 2007, 50, 3015. (b) Salituro, F. G.; Baker,
C. T.; Court, J. J.; Deininger, D. D.; Kim, E. E.; Li, B.; Novak, P. M.; Rao,
B. G.; Pazhanisamy, S.; Porter, M. D.; Schairer, W. C.; Tung, R. D. Bioorg.
Med. Chem. Lett. 1998, 8, 3637. (c) Spaltenstein, A.; Almond, M. R.; Bock,
W. J.; Cleary, D. G.; Furfine, E. S.; Hazen, R. J.; Kazmierski, W. M.;
Salituro, F. G.; Tung, R. D.; Wright, L. L. Bioorg. Med. Chem. Lett. 2000,
10, 1159. (d) Kazmierski, W. M.; Furfine, E.; Gray-Nunez, Y.; Spaltenstein,
A.; Wright, L. Bioorg. Med. Chem. Lett. 2004, 14, 5685. (e) Heidempergher,
F.; Pillan, A.; Pinciroli, V.; Vaghi, F.; Arrigoni, C.; Bolis, G.; Caccia, C.;
Dho, L.; McArthur, R.; Varasi, M. J. Med. Chem. 1997, 40, 3369. (f)
Reichard, G. A.; Stengone, C.; Paliwal, S.; Mergelsberg, I.; Majmundar,
S.; Wang, C.; Tiberi, R.; McPhail, A. T.; Piwinkski, J. J.; Shih, N.-Y. Org.
Lett. 2003, 5, 4249. (g) 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. (h) 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.
(1) Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed. 1998,
37, 2580.
10.1021/ol900730w CCC: $40.75
Published on Web 05/18/2009
 2009 American Chemical Society

We initially targeted N-δ-allenyl ureas as substrates and
cationic gold(I) complexes as catalysis for allene dihy-
droamination. δ-Allenyl ureas were targeted as substrates
both to control the regioselectivity of allene hydroamination
and to render the challenging alkene hydroamination step
intramolecular. Cationic gold(I) complexes were targeted as
catalysts owing to the high activity of these complexes
toward the hydroamination of both allenes12 and alkenes13
with carboxamide derivatives. An initial experiment was
encouraging, and treatment of the N-2,2-diphenyl-5,6-hep-
tadienyl urea 1 with a catalytic 1:1 mixture of the gold
phosphine complex (2)AuCl [2 ) P(t-Bu)2-o-biphenyl] and
AgOTf (5 mol %) in CH2Cl2 at room temperature for 24 h
led to complete consumption of 1 to form an 4:1 mixture of
vinyl piperidine derivative 3 and bicyclic imidazolidin-2-
one 4 (Table 1, entry 1).
1:1 mixture of AgPF6 and (2)AuCl led to formation of a
1:16 mixture of 3:4 after 2 h, the latter as a 11:1 diastere-
omeric mixture (Table 1, entry 8). Substitution of (5)AuCl
for (2)AuCl led to further increase in both the selectivity
and diastereoselectivity of dihydroamination (Table 1, entry
9).14
The effectiveness of AgPF6 relative to closely related silver
salts as a cocatalyst for the gold-catalyzed dihydroamination
of 1 was mirrored in the gold(I)-catalyzed conversion of 3
to 4 (Table 2). Treatment of 3 with a catalytic 1:1 mixture
Table 2. Effect of Counterion on the Gold(I)-Catalyzed
Conversion of 3 to 4
Table 1. Effect of Ligand and Counterion on the
Gold(I)-Catalyzed Dihydroamination of 1
.
entry
X
time (h)
convna (%)
1
2
3
4
SbF6
ClO4
BF4
24
24
24
2
52
66
48
PF6
>98
a
1
Determined by H NMR analysis of the crude reaction mixture.
of (5)AuCl and AgSbF6, AgClO4, or AgBF4 at room
temperature for 24 h led to partial (48-66%) conversion
(Table 2, entries 1-3). In contrast, conversion of 3 to 4 was
complete within 2 h at room temperature in the presence of
a catalytic 1:1 mixture of (5)AuCl and AgPF6 (Table 2, entry
4).
In a preparative-scale experiment, reaction of 1 with a
catalytic 1:1 mixture of (5)AuCl and AgPF6 (5 mol %) at
room temperature for 2 h led to isolation of 4 in 93% yield
with g98% diastereomeric purity (Table 3, entry 1). The
cis-relationship of the tertiary hydrogen atom and the
exocyclic methyl group of 4 was assigned unambiguously
by X-ray crystallography (see the Supporting Information).
In addition to 1, N-δ-allenyl ureas that possessed an
N′-phenyl (6), N’′4-methoxyphenyl (7), or N′-benzyl (8)
group underwent gold(I)-catalyzed intramolecular dihy-
droamination to form polycyclic imidazolidin-2-ones 9-11
in excellent yield as single diastereomers (Table 3, entries
2-4). The N-5,6-heptadienyl urea 12 that lacked substitution
at the 2-position of the heptadienyl chain and the heteroatom-
substituted N-δ-allenyl urea derivatives 13 and 14 underwent
gold-catalyzed intramolecular dihydroamination to form
imidazolidin-2-ones 15-17 in good yield as single diaster-
eomers (Table 3, entries 5-7). The N-5,6-heptadienyl urea
18 that possessed a single methyl group at the 4-position of
the heptadienyl chain underwent gold(I)-catalyzed dihy-
droamination to form a separable ∼3:1 mixture of diaster-
eomeric bicyclic imidazolidin-2-ones. From this mixture,
imidazolidin-2-one 19 was isolated in 70% yield with g98%
a
1
Determined by H NMR analysis of the crude reaction mixture.
Optimization of the gold(I)-catalyzed dihydroamination of
1 revealed the pronounced effect of the silver salt, in
particular AgPF6, on the conversion of 3 to 4 (Table 1).14
Employment of AgSbF6, AgClO4, AgOAc, or AgBF4 in
combination with either phosphine catalyst (2)AuCl or the
N-heterocyclic carbene complex (5)AuCl [5 ) 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidine] led to predominant
formation of 3 after 24 h at room temperature (Table 1,
entries 2-7). In sharp contrast, treatment of 1 with a catalytic
2672
Org. Lett., Vol. 11, No. 12, 2009

Scheme 1
Table 3. Intramolecular Dihydroamination of N-γ- and
N-δ-Ureas Catalyzed by a Mixture of (5)AuCl (5 mol %) and
AgPF6 (5 mol %) in CH2Cl2 at Room Temperature
Outer-sphere pathways for the gold(I)-catalyzed hydro-
functionalization of C-C multiple bonds have been proposed
on the basis of stereochemical16 and computational analy-
ses.17 On the basis of these precedents, we propose that the
gold(I)-catalyzed dihydroamination of N-allenyl ureas occurs
via two successive outer-sphere C-N bond forming pro-
cesses (Scheme 2). In the specific case of the gold(I)-
Scheme 2
catalyzed conversion of 1 to 4, outer-sphere attack of the
internal nitrogen atom on gold π-allene complex I followed
a Ar ) 4-C6H4NO2 unless noted otherwise. b Isolated material of >95%
purity with g98% diastereomeric purity. c Crude reaction mixture consisted
of a ∼3:1 mixture of diastereomers. The minor diastereomer of 19 (epi-19)
was epimeric at the methyl-bound stereocenter of the piperidine ring (see
the Supporting Information).
(3) For early approaches to alkene dihydroamination that employ a
stoichiometric amount of transition metal or heavy metal salt, see: (a)
Backvall, J.-E. Tetrahedron Lett. 1978, 19, 163. (b) Aranda, V. G.;
Barluenga, J.; Aznar, F. Synthesis 1974, 504. (c) Barluenga, J.; Aznar, F.;
de Mattos, M. C. S.; Kover, W. B.; Garcia-Granda, S.; Pe´rez-Carren˜o, E.
J. Org. Chem. 1991, 56, 2930. (d) Chong, A. O.; Oshima, K.; Sharpless,
K. B. J. Am. Chem. Soc. 1977, 99, 3420. (e) Becker, P. N.; White, M. A.;
Bergman, R. G. J. Am. Chem. Soc. 1980, 102, 5676.
diasteromeric purity (Table 3, entry 8). The relative config-
uration of 19 was established by NOESY analysis (see the
Supporting Information).
(4) de Figueiredo, R. M. Angew. Chem., Int. Ed. 2009, 48, 1190.
(5) Cochran, B. M.; Michael, F. E. Org. Lett. 2008, 10, 5039.
(6) (a) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem. Soc. 2005,
127, 11250. (b) Zawaba, T. P.; Chelmer, S. R. Org. Lett. 2007, 9, 2035.
(7) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem.
Soc. 2005, 127, 7308.
N-γ-Allenyl ureas also underwent gold(I)-catalyzed dihy-
droamination to form bicyclic imidazolidin-2-ones, although
higher catalyst loading and considerably higher reaction
temperature was required. Higher reaction temperature, in
turn, required employment of the less active but more
thermally robust gold phosphine complex (2)AuCl in place
of (5)AuCl. In an optimized procedure (see the Supporting
Information), reaction of N-γ-allenyl urea 20 with a catalytic
mixture of (2)AuCl (10 mol %) and AgPF6 (50 mol %) in
dioxane at 120 °C for 96 h led to exclusive formation of
imidazolidin-2-one 21, which was isolated in 86% yield with
g98% diastereomeric purity (Scheme 1).15 N-2,2-Diphenyl-
4,5-hexadienyl urea 22 also underwent dihydroamination
under these conditions to form 23 in 82% isolated yield with
96% diastereomeric purity (Scheme 1).
(8) (a) Streuff, J.; Ho¨velmann, C. H.; Nieger, M.; Mun˜iz, K. J. Am.
Chem. Soc. 2005, 127, 14586. (b) Mun˜iz, K.; Ho¨velmann, C. H.; Campos-
Go´mez, E.; Barluenga, J.; Gonza´lez, J. M.; Streuff, J.; Nieger, M. Chem.
Asian J. 2008, 3, 776. (c) Mun˜iz, K.; Ho¨velmann, C. H.; Streuff, J. J. Am.
Chem. Soc. 2008, 130, 763. (d) Mun˜iz, K.; Streuff, J.; Cha´vez, P.;
Ho¨velmann, C. H. Chem. Asian J. 2008, 3, 1248. (e) Mun˜iz, K. J. Am.
Chem. Soc. 2007, 129, 14542. (f) Ho¨velmann, C. H.; Streuff, J.; Brelot, L.;
Mun˜iz, K. Chem. Commun 2008, 2334.
(9) Mun˜iz, K.; Streuff, J.; Ho¨velmann, C. H.; Nu´n˜ez, A. Angew. Chem.,
Int. Ed. 2007, 46, 7125.
(10) (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,
11688. (c) Xu, L.; Du, H.; Shi, Y. J. Org. Chem. 2007, 72, 7038. (d) Xu,
L.; Shi, Y. J. Org. Chem. 2008, 73, 749.
(11) Zhao, B.; Du, H.; Shi, Y. Org. Lett. 2008, 10, 1087.
(12) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer,
R. A. J. Am. Chem. Soc. 2006, 128, 9066.
Org. Lett., Vol. 11, No. 12, 2009
2673

by proton transfer/protodeauration of the resulting alkenyl
gold species II would form 3 (Scheme 2). Outer-sphere attack
of the second nitrogen atom on the gold π-alkene complex
III followed by proton transfer/protodeauration of alkyl gold
species IV would then form 4. The origin of the high
diastereoselectivity of gold(I)-catalyzed dihydroamination
remains unclear. Diastereoselectivity may be determined
either by the conversion of III to IV in the event that C-N
bond formation is irreversible or by the conversion of IV to
4 in the case of reversible C-N bond formation followed
by irreversible protodeauration.17
In summary, we have developed effective Au(I)-catalyzed
protocols for the intramolecular dihydroamination of γ- and
δ-allenyl ureas to form bicyclic imidazolidin-2-ones that
proceed in good yield with excellent diastereoselectivity. We
are currently working toward the development of more
effective and more general allene dihydroamination protocols
and toward the elucidation of the kinetics and mechanism
of gold(I)-catalyzed allene dihydroamination.
Acknowledgment is made to the NIH (GM-080422) and
Johnson & Johnson for support of this research and to the
NCBC (2008-IDG-1010) for support of the Duke University
NMR facility. We thank Marina G. Dickens (Department of
Chemistry, Duke University) for determining the X-ray
crystal structure of 4.
Supporting Information Available: Experimental pro-
cedures, analytical and spectroscopic data for allenyl ureas
and imidazolidin-2-ones, and X-ray crystallographic data for
4. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL900730W
(15) The beneficial effect of the high loading of AgPF6 is unclear.
Control experiments, however, ruled out the presence of a silver(I) or acid-
catalyzed pathway for intramolecular hydroamination of the 2-vinylpyrro-
lidine intermediate formed in the gold(I)-catalyzed dihydroamination of 22.
Furthermore, dihydroamination of 22 catalyzed by the silver-free complex
[(2)Au(NCArF)]+ SbF6- [NCArF ) Nt C-3,5-C6H3(CF3)2] was not signifi-
cantly less effective than was dihydroamination of catalyzed by (2)AuCl/
AgPF6 (see the Supporting Information).
(13) (a) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45,
1747. (b) Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2006, 8, 5303. (c)
Bender, C. F.; Widenhoefer, R. A. Chem. Commun. 2006, 4143.
(16) (a) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2006, 128, 9066. (b) Zhang, Z.;
Widenhoefer, R. A. Org. Lett. 2008, 10, 2079. (c) Kennedy-Smith, J. J.;
Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526. (d) Zhang,
J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798. (e) Hashmi,
A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391.
(f) Liu, Y.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409.
(g) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798.
(17) Kova´cs, G.; Ujaque, G.; Lledo´s, A. J. Am. Chem. Soc. 2008, 130,
853.
(14) Treatment of 1 with either AgPF6 or (5)AuCl alone or with a
mixture of AgPF6 and 5 or HBF4 and 5 in CH2Cl2 led to no detectable
formation of either 3 or 4 after 2 h at room temperature. Furthermore, silver
was not required for efficient dihydroamination; treatment of 6 with a
-
catalytic amount of [(5)Au(NCArF)]+ SbF6 [NCArF ) Nt C-3,5-
C6H3(CF3)2] (5 mol %) in CH2Cl2 for 16 h led to quantitive formation of 9
(see the Supporting Information).
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Org. Lett., Vol. 11, No. 12, 2009