Room temperature hydroamination of N-alkenyl ureas catalyzed by a gold(I) N-heterocyclic carbene complex

Article abstract of DOI:10.1021/ol062107i

Treatment of an N-4-pentenyl or N-5-hexenyl urea with a catalytic 1:1 mixture of a gold(I) N,N-diaryl imidazol-2-ylidine complex and AgOTf at or near room temperature leads to intramolecular exo-hydroamination to form the corresponding nitrogen heterocycle in excellent yield.

Full text of DOI:10.1021/ol062107i

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5303-5305
Room Temperature Hydroamination of
N-Alkenyl Ureas Catalyzed by a Gold(I)
N-Heterocyclic Carbene Complex
Christopher F. Bender and Ross A. Widenhoefer*
P. M. Gross Chemical Laboratory, Duke UniVersity,
Durham, North Carolina 27708-0346
rwidenho@chem.duke.edu
Received August 26, 2006
ABSTRACT
Treatment of an N-4-pentenyl or N-5-hexenyl urea with a catalytic 1:1 mixture of a gold(I) N,N-diaryl imidazol-2-ylidine complex and AgOTf at
or near room temperature leads to intramolecular exo-hydroamination to form the corresponding nitrogen heterocycle in excellent yield.
Saturated nitrogen heterocycles constitute an important class
of naturally occurring and biogically active molecules.1 The
addition of the N-H bond of an amine or amide derivative
across the CdC bond of a pendent alkene (hydroamination)
has received considerable attention as an atom-economical
and potentially expedient route to the synthesis of nitrogen
heterocycles.2 However, despite significant effort in this area,
the intramolecular hydroamination of unactivated alkenes
remains problematic.2 Although rare earth,3 alkali,4 and group
45 metal complexes catalyze the intramolecular hydro-
amination of unactivated alkenes, the synthetic utility of these
transformations is compromised by the excessive oxophilicity
of the catalysts. Conversely, intramolecular hydroamination
of unactivated alkenes catalyzed by late transition metal
complexes typically requires either forcing conditions,6 a
sulfonamide nucleophile,7 or a conjugated alkenyl moiety.8,9
In response to the limitations associated with the intra-
molecular hydroamination of unactivated alkenes, we re-
cently reported the intramolecular hydroamination of N-
alkenyl carbamates catalyzed by a mixture of the gold(I)
phosphine complex Au[P(t-Bu)2(o-biphenyl)]Cl (1) and
AgOTf.10,11 As an example, reaction of 2a with a catalytic
1:1 mixture of 1 and AgOTf (5 mol %) in dioxane at 60 °C
(1) (a) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773. (b) Michael, J. P.
Nat. Prod. Rep. 2001, 18, 520. (c) Mitchinson, A.; Nadin, A. J. Chem.
Soc., Perkin Trans. 1 2000, 2862.
(2) (a) Beller, M.; Tillack, A.; Seayad, J. In Transition Metals for Organic
Synthesis, 2nd ed.; Wiley-VCH: Weinheim, 2004; pp 403-414. (b) Muller,
T. E.; Beller, M. Chem. ReV. 1998, 98, 675. (c) Beller, M.; Seayad, J.;
Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368. (d) Brunet, J.
J.; Neibecker, D. In Catalytic Heterofunctionalization; Togni, A., Gru¨tz-
macher, H., Eds.; Wiley-VCH: Weinheim, 2001; pp 91-142. (e) Pohlki,
F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104.
(3) (a) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673. (b) Riegert,
D.; Collin, J.; Meddour, A.; Schulz, E.; Trifonov, A. J. Org. Chem. 2006,
71, 2514. (c) Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 4391. (d)
Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737. (e) Gribkov, D. V.;
Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748.
(4) Crimmin, M. R.; Casely, I. J.; Hill, M. S. J. Am. Chem. Soc. 2005,
127, 2042.
(6) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127,
1070.
(7) (a) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128,
1798. (b) Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707. (c)
Komeyama, K.; Morimoto, T.; Takaki, K. Angew. Chem., Int. Ed. 2006,
45, 2938.
(8) (a) Tiamia, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 6042.
(b) Sakai, N.; Ridder, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
8134.
(9) For recent examples of the zinc-catalyzed intramolecular hydroami-
nation of unactivated alkenes, see: (a) Zulys, A.; Dochnahl, M.; Hollmann,
D.; Lo¨hnwitz, K.; Herrmann, J.-S.; Roesky, P. W.; Blechert, S. Angew.
Chem., Int. Ed. 2005, 44, 7794. (b) Dochnahl, M.; Pissarek, J.-W.; Blechert,
S.; Lo¨hnwitz, K.; Roesky, P. W. Chem. Commun. 2006, 3405. (c) Meyer,
N.; Lo¨hnwitz, K.; Zulys, A.; Roesky, P. W.; Dochnahl, M.; Blechert, S.
Organometallics 2006, 25, 3730.
(5) (a) Mu¨ller, C.; Loos, C.; Schulenberg, N.; Doye, S. Eur. J. Org. Chem.
2006, 2499. (b) Kim H.; Lee, P. H.; Livinghouse, T. Chem. Commun. 2005,
5205. (c) Thompson, R. K.; Bexrud, J. A.; Schafer, L. L. Organometallics
2006, 25, 4069.
(10) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45, 1747.
10.1021/ol062107i CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/14/2006

Table 1. Hydroamination of 2a-2c Catalyzed by a 1:1
Mixture of Au(4)Cl and AgOTf
Initial hydroamination experiments employing Au(4)Cl as
a precatalyst were encouraging. Treatment of N-4-pentenyl
derivatives 2a-2c with a 1:1 mixture of Au(4)Cl and AgOTf
at 45 °C for 15 h in each case led to complete consumption
of 2 and isolation of the corresponding pyrrolidine 3 in g93%
entry
R
temp time(h) convn (%)a yield (%)b
1
2
3
4
5
6
Cbz (a)
Ac (b)
CONHPh (c) 45 °C
Cbz (a)
Ac (b)
CONHPh (c) rtc
45 °C
45 °C
15
15
15
18
18
18
100
100
100
20
96
99
93
rtc
rtc
83
100
83
96
Table 2. Hydroamination of N-Alkenyl Ureas Catalyzed by a
1:1 Mixture of Au(4)Cl and AgOTf (5 mol %) at Room
Temperature17 for 15-24 h
a Determined by 1H NMR analysis of the crude reaction mixture.
b Isolated material of >95% purity. c 22-24 °C.
for 22 h led to isolation of pyrrolidine 3a in 97% yield (eq
1). N-Alkenyl carboxamides and ureas such as 2b and 2c
also underwent efficient hydroamination in the presence of
1/AgOTf, although somewhat higher reaction temperature
(80 °C) was required (eq 1).12 Lower reaction temperature
in each case led to incomplete conversion.
For some time we have sought to identify more active
and more general catalyst systems for the intramolecular
hydroamination of unactivated alkenes. We noted that
sterically hindered, electron-rich phosphines such as P(t-Bu)2-
(o-biphenyl) were particularly effective supporting ligands
for gold-catalyzed hydroamination.10 As is the case with
electron-rich phosphines, N-heterocyclic carbenes are strong
σ-donors that form stable compounds with a diverse range
of transition metals13 including gold(I).14 Furthermore, a
number of these ligands, in particular the commercially
available 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine
(4), are highly sterically hindered.15 These characterisitics
suggested that 4 might also function as an effective sup-
porting ligand for gold-catalyzed hydroamination.16 Indeed,
here we report that Au(4)Cl is an exceptionally active
precatalyst for the intramolecular hydroamination of N-
alkenyl ureas.
(11) For the Pd(II)-catalyzed intramolecular hydroamination of N-alkenyl
carbamates, see: Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006,
128, 4246.
(12) Bender, C. F.; Widenhoefer, R. A. Chem. Commun. 2006, 4143.
(13) (a) Hermann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (b)
Crudden, C. M.; Allen, D. P. Coord. Chem. ReV. 2004, 248, 2247.
(14) de Fre´mont, P.; Scott, N. M.; Stevens, E. D.; Nolan, S. P.
Organometallics 2005, 24, 2411.
(15) Dorta, R.; Stevens, E. D.; Scott, N. M.; Costablile, C.; Cavallo, L.;
Hoff, C. D.; Nolan, S. P. J. Am. Chem. Soc. 2005, 127, 2485.
a Major diastereomer is shown. b Solvent: A ) dioxane, B ) MeOH, C
) MeOH/H2O (95/5). c Isolated product of g95% purity. d Reaction run
with 1 mol % catalyst loading. e Reaction run exposed to atmosphere.
f Reaction run at 45 °C with 10 mol % catalyst loading. g Reaction run at
45 °C. h Reaction run at 45 °C with 10 mol % catalyst loading for 43 h.
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Org. Lett., Vol. 8, No. 23, 2006

yield (Table 1, entries 1-3). However, the corresponding
room temperature hydroamination of carbamate 2a or car-
boxamide 2b failed to reach completion after 18 h (Table 1,
entries 4 and 5).17 Conversely, reaction of urea 2c with a
1:1 mixture of Au(4)Cl and AgOTf at room temperature for
18 h led to complete consumption of 2c and isolation of 3c
in 96% yield (Table 1, entry 6).18 Subsequent experimentation
revealed that employment of methanol as solvent in place
of dioxane led to a ∼2-fold increase in the rate of hydro-
amination.
Both N′-aryl and N′-alkyl N-4-pentenyl ureas underwent
intramolecular hydroamination at room temperature in high
yield in the presence of a catalytic amount of Au(4)Cl/AgOTf
(Table 2, entries 1-4). The Au(4)Cl/AgOTf catalyst system
was sufficiently active such that efficient hydroamination was
realized with 1 mol % of the catalyst mixture (Table 2, entry
5). Furthermore, neither the rate nor the yield of hydro-
amination was affected by the presence of a large excess of
water or air in the reaction mixture (Table 2, entries 6 and
7). Gold-catalyzed hydroamination of 4-pentenyl ureas
monosubstituted at the C(1) or C(2) position formed sub-
stituted pyrrolidines that possessed a cis-2,5 or cis-2,4
substitution pattern, respectively, with up to 5.5:1 diaste-
reoselectivity (Table 2, entries 8-12). Noteworthy was that
the diastereoselectivity of these transformations was im-
proved relative to the hydroamination of the corresponding
N-4-pentenyl carboxamides catalyzed by 1/AgOTf (e1.8:
1).12 Gold-catalyzed hydroamination of alkenyl ureas also
tolerated substitution at the internal olefinic carbon atom and
was effective for the cyclization of an unsubstituted N-4-
pentenyl urea, although more forcing conditions were
required (Table 2, entries 13 and 14). A 5-hexenyl urea also
underwent room temperature hydroamination in the presence
of Au(4)Cl/AgOTf to form the corresponding piperidine
derivative in excellent yield (Table 2, entry 15).
In summary, we have reported the first application of a
gold(I) carbene complex as a catalyst for the hydroamination
of unactivated alkenes. The resulting catalyst system is highly
active for the exo-hydroamination of N-4-pentenyl and N-5-
hexenyl ureas to form the corresponding nitrogen hetero-
cycles in excellent yield with good regioselectivity and up
to 5.5:1 diasteroselectivity.
(16) For recent examples of the application of gold N-heterocyclic carbene
complexes as catalysts for organic transformations, see: (a) Marion, N.;
de Fre´mont, P.; Lemie`re, G.; Stevens, E. D.; Fensterbank, L.; Malacria,
M.; Nolan, S. P. Chem. Commun. 2006, 2048. (b) Fructos, M. R.; Belderrain,
T. R.; de Fre´mont, P.; Scott, N. M.; Nolan, S. P.; D´ıaz-Requejo, M. M.;
Pe´rez, P. J. Angew. Chem., Int. Ed. 2005, 44, 5284. (c) Fructos, M. R.; de
Fre´mont, P.; Nolan, S. P.; D´ıaz-Requejo, M. M.; Pe´rez, P. J. Organometallics
2006, 25, 2237. (d) Schneider, S. K.; Herrmann, W. A.; Herdtweck, E. Z.
Anorg. Allg. Chem. 2003, 629, 2363.
Acknowledgment. The authors acknowledge the NSF
(CHE-0304994 and CHE-0555425), the Petroleum Research
Fund (43636-AC1), adminstered by the American Chemical
Society, and Johnson & Johnson for support of this research.
C.F.B. thanks Duke University for a Charles R. Hauser
Fellowship.
(17) Room temperature ranged from 22 to 24 °C.
(18) Treatment of 2c with HOTf (15 mol %), Au(4)Cl (15 mol %), or
AgOTf (15 mol %) in methanol at room temperature for 15 h led to no
detectable consumption of 2c by 1H NMR analysis. For an analysis of the
role of HOTf in the intramolecular hydroamination of unactivated alkenes
with sulfonamides, see: Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.;
Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179.
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OL062107I
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