Aerobic intramolecular oxidative amination of alkenes catalyzed by NHC-coordinated palladium complexes

Article abstract of DOI:10.1021/ol060327q

Palladium(II) complexes bearing a single N-heterocyclic carbene ligand serve as effective catalysts for the aerobic oxidative cyclization of alkenes with pendant sulfonamides. The use of carboxylic acid cocatalysts (AcOH and PhCO₂H) often leads

Full text of DOI:10.1021/ol060327q

ORGANIC
LETTERS
2
006
Vol. 8, No. 11
257-2260
Aerobic Intramolecular Oxidative
Amination of Alkenes Catalyzed by
NHC-Coordinated Palladium Complexes
2
Michelle M. Rogers, Johanna E. Wendlandt, Ilia A. Guzei, and Shannon S. Stahl*
Department of Chemistry, UniVersity of Wisconsin, Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706
stahl@chem.wisc.edu
Received February 7, 2006
ABSTRACT
Palladium(II) complexes bearing a single N-heterocyclic carbene ligand serve as effective catalysts for the aerobic oxidative cyclization of
alkenes with pendant sulfonamides. The use of carboxylic acid cocatalysts (AcOH and PhCO H) often leads to significant improvements in
catalyst stability and product yield and enables catalytic turnover to be achieved with air, rather than pure oxygen gas, as the source of O
2
2
.
Palladium-catalyzed, Wacker-type oxidative cyclization of
alkenes represents an attractive strategy for the synthesis of
for the intramolecular oxidative amination of alkenes. The
reactions can proceed with air, rather than pure oxygen gas,
1
heterocycles. This reaction class, which has rich historical
2
precedent, has been the subject of considerable recent
(3) (a) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119,
063-5064. (b) Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998,
3, 5071-5075. (c) Uozumi, Y.; Kyota, H.; Kato, K.; Ogasawara, M.;
5
6
attention. Current efforts are especially focused on the
3
,4
development of asymmetric reactions, new synthetic
Hayashi, T. J. Org. Chem. 1999, 64, 1620-1625. (d) Arai, M. A.; Kuraishi,
M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907-2908. (e) Trend,
R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int.
Ed. 2003, 42, 2892-2895. (f) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B.
M. J. Am. Chem. Soc. 2005, 127, 17778-17788.
5
,6
transformations (e.g., 1,2-difunctionalization of alkenes),
and methods that employ molecular oxygen as the terminal
oxidant.7 Here, we report the use of N-heterocyclic carbene
,8
II
(4) For early studies directed toward asymmetric Wacker-type cyclization
reactions, see: (a) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J. Am.
Chem. Soc. 1981, 103, 2318-2323. (b) Hosokawa, T.; Okuda, C.;
Murahashi, S.-I. J. Org. Chem. 1985, 50, 1282-1287.
(
NHC)-coordinated Pd catalysts, (NHC)Pd-(O
2 3 2 2
CCF ) (OH ),
(
1) (a) Hegedus, L. S. In ComprehensiVe Organic Synthesis; Semmelhack,
M. F., Ed.; Pergamon Press: Elmsford, NY, 1991; Vol. 4, pp 551-569.
b) Hosokawa, T.; Murahashi, S.-I. In Handbook of Organopalladium
(5) See, for example: (a) Manzoni, M. R.; Zabawa, T. P.; Kasi, D.;
Chemler, S. R. Organometallics 2004, 23, 5618-5621. (b) Lira, R.; Wolfe,
J. P. J. Am. Chem. Soc. 2004, 126, 13906-13907. (c) Ney, J. E.; Wolfe, J.
P. Angew. Chem., Int. Ed. 2004, 43, 3605-3608. (d) Yang, Q.; Ney, J. E.;
Wolfe, J. P. Org. Lett. 2005, 7, 2575-2578. (e) Bertrand, M. B.; Wolfe, J.
P. Tetrahedron 2005, 61, 6447-6459. (f) Ney, J. E.; Hay, M. B.; Yang,
Q.; Wolfe, J. P. AdV. Synth. Catal. 2005, 347, 1614-1620. (g) Bar, G. L.
J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2005,
127, 7308-7309. (h) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem.
Soc. 2005, 127, 7690-7691. (i) Streuff, J.; H o¨ velmann, C. H.; Nieger, M.;
Mu n˜ iz, K. J. Am. Chem. Soc. 2005, 127, 14586-14587.
(
Chemistry for Organic Synthesis; Negishi, E., de Meijere, A., Eds.; John
Wiley and Sons: New York, 2002; Vol. 2, pp 2169-2192. (c) Hosokawa,
T. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., de Meijere, A., Eds.; John Wiley and Sons: New York, 2002;
Vol. 2, pp 2211-2225. (d) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104,
2
285-2309.
(
2) (a) Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc.
1
976, 98, 2674-2676. (b) Hosokawa, T.; Miyagi, S.; Murahashi, S.-I.;
Sonoda, A. J. Org. Chem. 1978, 43, 2752-2757. (c) Hegedus, L. S.; Allen,
G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800-
(6) For recent Cu-mediated carboamination methods, see: (a) Sherman,
E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O. Org. Lett. 2004, 6, 1573-
1575. (b) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem. Soc. 2005,
127, 11250-11251.
5
807. (d) Hegedus, L. S.; Allen, G. F.; Olsen, D. J. J. Am. Chem. Soc.
980, 102, 3583-3587. (e) Hegedus, L. S.; McKearin, J. M. J. Am. Chem.
1
Soc. 1982, 104, 2444-2451.
1
0.1021/ol060327q CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/27/2006

liminary mechanistic insights into the oxidative amination
of styrene prompted us to evaluate the NHC-coordinated Pd
Table 1. Catalyst Screening Data for the Aerobic Oxidative
Amination of 1a
1
0a,11
complex, [(IPr)PdCl
complex proved to be less effective than other Pd catalysts,
such as (Et N) PdCl . Nevertheless, prospects for the use of
2 2
] , in such reactions;
however, this
3
2
2
NHC ligands in Pd-catalyzed oxidation reactions have been
clearly demonstrated by Sigman and co-workers.12 In par-
ticular, they reported a new class of NHC-Pd complexes,
(
NHC)Pd(O
for aerobic alcohol oxidation.
that these complexes are also effective for the oxidative
2 2 2
CR) (OH ), that are highly effective catalysts
%
of 2/3b
yield
1
2a,d
entry
catalyst
[IMesPdCl
IMesPd(OAc)
IMesPd(TFA)
IPrPd(TFA)
solvent
additive
Recently, Mu n˜ iz showed
1
2
3
4
5
6
7
8
9
2
]
2
toluene
toluene
toluene
toluene
toluene 3A MS
toluene 1 equiv of NaOAc
toluene 1 equiv of KH
toluene 1 equiv of MgO
toluene 1 equiv of NaHCO
toluene 1 equiv of KOtBu
toluene 20% pyridine
0/0
83/7
88/1
85/1
35/2
88/7
81/1
70/3
75/2
42/0
20/4
34/0
94/0
91/4
8
f
cyclization of several o-allylphenol substrates. These ex-
amples highlight propects for the use of NHC ligands in
catalytic oxidation reactions.
2
OH
2
2
OH
2
1
3
2
OH
2
IMesPd(TFA)
IMesPd(TFA)
IMesPd(TFA)
IMesPd(TFA)
IMesPd(TFA)
IMesPd(TFA)
IMesPd(TFA)
IMesPd(TFA)
2
2
2
2
2
2
2
2
OH
2
2
2
2
2
2
2
We intiated our studies by evaluating IMes- and IPr-
OH
OH
OH
OH
OH
OH
OH
11
coordinated Pd complexes as potential catalysts for the
2 4
PO
aerobic oxidative cyclization of the cis-crotyl tosylanilide
substrate 1 (Table 1). To ensure maximum data reliability,
we independently synthesized the Pd complexes used in this
study rather than preparing them in situ from the corre-
sponding PdX
The (IMes)Pd(O
3
10
11
12
13
14
15
16
17
18
19
20
21
source and imidazolium salt of the carbene.
CCF (OH ) complex, which is the most
2
toluene 10% CF
3
CO
2
H
2
IMesPd(TFA)
IMesPd(TFA)
2
OH
OH
2
2
toluene 10% AcOH
toluene 20% PhCO
toluene
)
2
3
2
2
2
2
H
effective catalyst, was also characterized by X-ray crystal-
lography (Figure 1).
c
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
54/5
14
toluene 20% PhCO
toluene 20% pyridine
CH CN
2
H
45/0c
80/0
18/0
34/0
46/0
2/0
IMesPd(TFA)
IMesPd(TFA)
IMesPd(TFA)
IMesPd(TFA)
2
2
2
2
OH
OH
OH
OH
2
2
2
2
3
DME
DMF
CHCl
3
a
Reaction conditions: substrate (100 µmol), Pd (5 µmol), additive, 1
b 1
mL of solvent, 1 atm of O2, 80 °C, 4 h. H NMR yield, internal standard
1,3,5-trimethoxybenzene. No additional products are generally observed;
the remainder is unreacted starting material. An unidentified byproduct
15-20%, based on mass balance) is also obtained.
)
c
(
as the source of oxidant if carboxylic acid cocatalysts are
employed in the reaction, and they also constitute the first
catalytic application of Pd complexes bearing a new class
2 3 2 2
Figure 1. Molecular structure of (IMes)Pd(O CCF ) (OH ). Hy-
drogen atoms are omitted for clarity. Thermal ellipsoids are shown
at 30% probability.
9
of seven-membered NHC ligands that we recently described.
Ongoing studies in our laboratory are focused on the
development of dioxygen-coupled methods for both intra-
8
e,10
and intermolecular oxidative amination of alkenes.
Pre-
2 2
Pd-chloride complexes, [IMesPdCl ] (Table 1, entry 1)
and IMesPd(allyl)Cl (not shown), were ineffective as cata-
lysts; however, complexes with acetate or trifluoroacetate
(
7) For recent reviews describing direct dioxygen-coupled Pd-catalyzed
oxidative cyclization reactions, see: (a) Stahl, S. S. Angew. Chem., Int.
Ed. 2004, 43, 3400-3420. (b) Stoltz, B. M. Chem. Lett. 2004, 33, 362-
(TFA) as the anionic ligand were quite successful (entries
3
2
67. (c) Sigman, M. S.; Schultz, M. J. Org. Biomol. Chem. 2004, 2, 2551-
554. (d) Stahl, S. S. Science 2005, 309, 1824-1826.
(8) See, for example: (a) van Benthem, R. A. T. M.; Hiemstra, H.; van
(11) Abbreviations: IPr ) N,N′-bis(2,6-diisopropylphenyl)imidazol-2-
ylidine; IMes ) N,N′-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene; DMAP
) 4-(N,N′-dimethylamino)pyridine.
(12) (a) Jensen, D. R.; Schultz, M. J.; Mueller, J. A.; Sigman, M. S.
Angew. Chem., Int. Ed. 2003, 42, 3810-3813. (b) Jensen, D. R.; Sigman,
M. S. Org. Lett. 2003, 5, 63-65. (c) Mueller, J. A.; Goller, C. P.; Sigman,
M. S. J. Am. Chem. Soc. 2004, 126, 9724-9734. (d) Schultz, M. J.;
Hamilton, S. S.; Jensen, D. R.; Sigman, M. S. J. Org. Chem. 2005, 70,
3343-3352. (e) Cornell, C. N.; Sigman, M. S. J. Am. Chem. Soc. 2005,
127, 2796-2797.
Leeuwen, P. W. N. M.; Geus, J. W.; Speckamp, W. N. Angew. Chem., Int.
Ed. Engl. 1995, 34, 457-460. (b) R o¨ nn, M.; B a¨ ckvall, J.-E.; Andersson,
P. G. Tetrahedron Lett. 1995, 36, 7749-7752. (c) Larock, R. C.; Hightower,
T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584-
3
585. (d) Larock, R. C.; Pace, P.; Yang, H.; Russell, C. E.; Cacchi, S.;
Fabrizi, G. Tetrahedron 1998, 54, 9961-9980. (e) Fix, S. R.; Brice, J. L.;
Stahl, S. S. Angew. Chem., Int. Ed. 2002, 41, 164-166. (f) Mu n˜ iz, K. AdV.
Synth. Catal 2004, 346, 1425-1428.
(9) (a) Scarborough, C. C.; Grady, M. J. W.; Guzei, I. A.; Gandhi, B.
A.; Bunel, E. E.; Stahl, S. S. Angew. Chem., Int. Ed. 2005, 44, 5269-
272. (b) Scarborough, C. C.; Popp, B. V.; Guzei, I. A.; Stahl, S. S. J.
Organomet. Chem. 2005, 690, 6143-6155.
10) (a) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc.
(13) For a review of the use of NHCs in metal-catalyzed oxidation
reactions, see: Rogers, M. M.; Stahl, S. S. N-Heterocyclic Carbenes in
Transition Metal Catalysis; Glorius, F., Ed.; Springer: New York, 2006;
in press.
(14) For related crystallographically characterized (NHC)Pd(O2CR)2
complexes, see refs 9b, 12a, and 12c, and the following: Viciu, M. S.;
Stevens, E. D.; Petersen, J. L. Organometallics 2004, 23, 3752-3755.
5
(
2
003, 125, 12996-12997. (b) Brice, J. L.; Harang, J. E.; Timokhin, V. I.;
Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868-2869. (c)
Timokhin, V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 17888-17893.
2258
Org. Lett., Vol. 8, No. 11, 2006

2-4). Use of the more basic acetate ligand results in slightly
higher quantities of the 6-endo cyclization product 3, but
both anionic ligands enable formation of the dihydroindole
product 2 in >80% yield. The identity of the carbene ligand
Table 2. Intramolecular Oxidative Amination of Olefinic
Substrates
(
4
IMes vs IPr) has little effect on the reaction (entries 3 and
). Molecular sieves, which are commonly employed in Pd-
catalyzed aerobic oxidation reactions (entry 5), have a
15
detrimental effect on the reaction yield. More polar solvents
also were less effective (entries 18-21).
In the oxidative cyclization of o-allylphenols catalyzed by
8f
NHC-Pd complexes, it was noted that base (20 mol %
1
1
2 3
DMAP and 2 equiv Na CO ) was required to avoid side
reactions and maintain catalyst stability. In the current
amination reactions, however, anionic bases and pyridine
generally lead to inferior results (Table 1, entries 6-11). In
contrast, the best results are obtained under acidic conditions,
namely, in the presence of catalytic quantities of acetic or
benzoic acid (entries 13 and 14).
For comparison, palladium acetate (alone or with cocata-
lytic benzoic acid) is a moderately effective catalyst for the
reaction (Table 1, entries 15 and 16). Better results were
2
obtained with Pd(OAc) /pyridine (entry 17), a catalyst system
8
e
that we have described previously for such reactions. The
oxidative cyclization of 1, however, proceeds most ef-
fectively with the NHC-based catalysts.1
6
On the basis of these results, we employed 5 mol % of
2 2
(IMes)Pd(TFA) (OH ) with cocatalytic acetic acid as the
starting point to test the reactivity of other substrates.
Cyclization of a series of olefinic tosylamides proceeds in
good yield (Table 2). In scale-ups, we observed that yields
were often a few percent higher with benzoic acid as the
cocatalyst rather than acetic acid. Aromatic-ring substituents
have little effect on the success of the reaction, although the
p-chloro substrate (entry 3) reacts slightly faster than those
bearing a methyl substituent in the ortho or para position
a
Substrate (0.5 mmol), IMesPd(O2CCF3)2 (0.025 mmol), 5 mL of
b
c
toluene, 1 atm of O2. Acetic acid (0.10 mmol), 80 °C. Benzoic acid (0.10
mmol), 80 °C. d Sodium acetate (0.50 mmol), 80 °C. e Benzoic acid (0.10
mmol), 60 °C.
(entries 3 and 4). We have initiated mechanistic studies to
probe the origin of this effect.
An important goal in the development of aerobic oxidation
reactions is to identify conditions compatible with the use
Changing the degree of substitution on the alkene from
di- to trisubstituted has a detrimental influence. The trisub-
stituted alkene (entry 5) does not react effectively under
standard conditions; however, a moderate yield of the desired
product was obtained if the reaction was performed in the
presence of base (1 equiv of sodium acetate). The origin of
this acid/base effect is not presently understood. Alkyl
tosylamide substrates (entries 6-8) are generally less reactive
than the tosylanilides. The longer reaction times required for
these substrates partly reflects the lower temperature em-
ployed to obtain optimal yields. At higher temperatures,
competing substrate decomposition is observed. Geminal
disubstitution significantly improves substrate reactivity
of air as the source of O
Sigman et al. for the aerobic oxidation of alcohols,
2
. Building on insights reported by
12a,c
we
find that the oxidative cyclization of 1 proceeds successfully
when the reaction is performed under ambient air, but only
if acetic acid (or another carboxylic acid) is present as a
17,18
cocatalyst (eq 1).
When the cyclization of 1 under air is
(
entry 8); the analogue lacking gem-diphenyl substitution
attempted in the absence of carboxylic acid, formation of
palladium black and low yields are observed. The reaction
yields only trace product under similar conditions.
2
time under air is elongated relative to the pure-O conditions
(
15) For a discussion of molecular sieves in Pd-catalyzed aerobic
(cf. Table 2, entry 1), but final yields are virtually identical.
Despite the longer reaction time, this observation highlights
oxidation reactions, see: Steinhoff, B. A.; King, A. E.; Stahl, S. S. J. Org.
Chem. 2006, 71, 1861-1868.
(
16) The stability of the NHC-Pd complex during catalytic turnover
1
has been confirmed by monitoring the reaction in situ by H NMR
spectroscopy.
(17) The use of 5% Pd(OAc)2/20% PhCO2H as a catalyst under an air
atmosphere generates the product in 46% yield under identical conditions.
Org. Lett., Vol. 8, No. 11, 2006
2259

prospects for this important simplification of the conditions
for aerobic oxidative cyclization reactions.
Scheme 1. Proposed Catalytic Cycle for Intramolecular
Oxidative Amination of Alkenes Catalyzed by
We recently reported a series of Pd complexes bearing a
II
(
IMes)Pd (O
2
3
CCF )
2
new class of carbene ligands based on a seven-membered
9
heterocyclic ring, and the Pd(TFA)
2
complex 4 has been
9
b
characterized previously by X-ray crystallography. The
aerobic oxidative cyclization of 1 (eq 2) catalyzed by 4
investigated their reactivity with molecular oxygen.19a We
II
find that carboxylic acids promote the oxygenation of Pd -H
represents the first successful application of these seven-
membered carbenes as ancillary ligands in a catalytic
reaction. We are hopeful that ongoing efforts will lead to
the development of enantiomerically resolved analogues of
these ligands that will find use in asymmetric catalysis.
2
(i.e., the net reaction, C + O f F, Scheme 1). The origin
of this effect is not yet known, but it provides a possible
explanation for the improved catalyst performance in the
II
presence of carboxylic acids. The Pd -hydroperoxide prod-
1
9b
uct F can undergo subsequent protonolysis to release
A proposed catalytic cycle for these reactions is shown in
Scheme 1. Aminopalladation (A + 1 f B) generates the
heterocyclic ring and an intermediate alkyl-Pd(II) interme-
diate. Our recent study of Pd-catalyzed oxidative amination
of styrene suggests this step might be reversible.1 â-Hydride
hydrogen peroxide (which disproportionates into water and
2
O ) and catalytically active Pd(II), A.
In conclusion, we have demonstrated that NHC-coordi-
nated Pd complexes are effective catalysts for the intramo-
lecular oxidative amination of alkenes with molecular oxygen
as the stoichiometric oxidant. The beneficial effect of
carboxylic acid cocatalysts is noteworthy and is currently
the subject of a mechanistic study.
0c
II
elimination from B generates the product 2 and Pd -H
intermediate C. The precise role of the carboxylic acid
cocatalyst is not known, but we speculate that it plays an
important role in catalyst stabilization and reoxidation by
Acknowledgment. We thank C. C. Scarborough for
providing us with a sample of 4 and M. M. Konnick for
assistance with in situ NMR spectroscopic studies. This work
was supported by the NIH (RO1 GM67173) Dreyfus
Foundation (Teacher-Scholar Award) and a UW-Madison
Graduate School Technology Transfer Grant.
O
2
. In studies of aerobic alcohol oxidation catalyzed by
NHC-coordinated Pd complexes, Sigman et al. observed that
1
2c
carboxylic acids enhance the catalyst lifetime.
They
propose that the acid reacts reversibly with Pd(0) to form
Pd(II)-hydrides, which are less susceptible to decomposition
(
i.e., C S D, Scheme 1). In addition, they observe that low
Supporting Information Available: Experimental pro-
cedures, characterization data, and crystallographic data for
IMes)Pd(TFA) (OH ) (PDF and CIF). This material is
2 2
concentrations of acid increase the rate. Recently, we
prepared a series of NHC-coordinated Pd -H complexes and
II
(
available free of charge via the Internet at http://pubs.acs.org.
(18) Additional examples of air-promoted Pd-catalyzed oxidation reac-
tions are known. See, for example: (a) Larock, R. C.; Wei, L.; Hightower,
T. R. Synlett 1998, 522-524. (b) Bagdanoff, J. T.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2004, 43, 353-357. (c) Enquist, P.-A.; Lindh, J.; Nilsson,
P.; Larhed, M. Green Chem. 2006, 8, 338-343. (d) Beck, E. M.; Grimster,
N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528-2529.
OL060327Q
(19) (a) Konnick, M. M.; Gandhi, B. A.; Guzei, I. A.; Stahl, S. S. Angew.
Chem., Int. Ed. 2006, 45, 2904-2907. (b) Konnick, M. M.; Guzei, I. A.;
Stahl, S. S. J. Am. Chem. Soc. 2004, 126, 10212-10213.
2260
Org. Lett., Vol. 8, No. 11, 2006