Intramolecular Pd(II)-catalyzed aerobic oxidative amination of alkenes: Synthesis of six-membered N-heterocycles

Article abstract of DOI:10.1021/ol300030w

Use of a base-free Pd(DMSO)₂(TFA)₂ catalyst system enables the synthesis of six-membered nitrogen heterocycles via a Wacker-type aerobic oxidative cyclization of alkenes bearing tethered sulfonamides. Various heterocycles, including morpholines, piperidines, piperazines, and piperazinones, are accessible by this method.

Full text of DOI:10.1021/ol300030w

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1234–1237
Intramolecular Pd(II)-Catalyzed Aerobic
Oxidative Amination of Alkenes:
Synthesis of Six-Membered
N-Heterocycles
Zhan Lu and Shannon S. Stahl*
Department of Chemistry, University of Wisconsin;Madison, 1101 University Avenue,
Madison, Wisconsin 53706, United States
stahl@chem.wisc.edu
Received January 6, 2012
ABSTRACT
Use of a base-free Pd(DMSO)2(TFA)2 catalyst system enables the synthesis of six-membered nitrogen heterocycles via a Wacker-type aerobic
oxidative cyclization of alkenes bearing tethered sulfonamides. Various heterocycles, including morpholines, piperidines, piperazines, and
piperazinones, are accessible by this method.
Nitrogen heterocycles, such as morpholines, pipera-
zines, and piperidines, are ubiquitous in natural products
and pharmaceuticals, and they have been the focus of
extensive synthetic interest.1 PdII-catalyzed oxidative cy-
clization of alkenes represents an efficient route to
heterocycles,2 and many “Wacker-type” reactions of this
type are compatible with the use of O2 asthe stoichiometric
oxidant.3 Nevertheless, while many of these reactions are
effective for the formation of five-membered rings,2 few
general methods have been reported for the synthesis of
(3) For reviews of Pd(II)-catalyzed aerobic oxidation reactions,
including Wacker-type cyclizations, see: (a) Stahl, S. S. Angew. Chem.,
Int. Ed. 2004, 43, 3400–3420. (b) Sigman, M. S.; Jensen, D. R. Acc.
Chem. Res. 2006, 39, 221–229.
(1) (a) Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft,
F. L.; Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis-Stuttgart 2004, 641–
662. (b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127–2198.
(4) Studies of heterocyclization reactions often include six-membered
rings in the substrate scope, but routes to these products tend to be less
effective than those for five-membered rings. For representative exam-
ples of aminocyclization reactions (non-Wacker-type reactions) that
include six-membered ring formation, see: (a) Tamaru, Y.; Hojo, M.;
Kawamura, S.-i.; Yoshida, Z.-i. J. Org. Chem. 1986, 51, 4089–4090.
(b) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 6042–
6043. (c) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45,
1747–1749. (d) Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2007, 9, 3279–3282.
(e) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 4253–4271.
(f) Leathen, M. L.; Rosen, B. R.; Wolfe, J. P. J. Org. Chem. 2009, 74,
5107–5110. (g) Wu, L.; Qiu, S.; Liu, G. Org. Lett. 2009, 11, 2707–2710.
(h) Rice, G. T.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11707–11711.
(i) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354–16355.
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Rev. 2008, 108, 3174–3198. (d) Patil, N. T.; Yamamoto, Y. Chem. Rev.
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N. R.; Branco, L. C.; Gois, P. M. P.; Afonso, C. A. M.; Trindade, A. F.
Chem. Rev. 2009, 109, 2703–2802. (g) Majumdar, K. C.; Chattopadhyay,
B.; Maji, P. K.; Chattopadhyay, S. K.; Samanta, S. Heterocycles 2010, 81,
795–866.
(2) For representative reviews, see: (a) Hegedus, L. S. In Comprehen-
sive Organic Synthesis; Semmelhack, M. F., Ed.; Pergamon Press, Inc.:
Elmsford, NY, 1991; Vol. 4, pp 551ꢀ569. (b) Hosokawa, T.; Murahashi,
S.-I. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., de Meijere, A., Eds.; John Wiley and Sons, Inc.: New York, 2002;
Vol. 2, pp 2169ꢀ2192. (c) Hosokawa, T. In Handbook of Organopalla-
dium Chemistry for Organic Synthesis; Negishi, E., de Meijere, A., Eds.;
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(5) For representative Wacker-type reactions compatible with six-
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r
10.1021/ol300030w
Published on Web 02/22/2012
2012 American Chemical Society

six-membered and larger nitrogen heterocycles.4ꢀ6 Here,
we describe the application of a recently developed Pd-
(DMSO)2(TFA)2 catalystsystem(DMSO = dimethylsulf-
oxide, TFA = trifluoroacetate)7,8 for the synthesis of a
variety of six-membered nitrogen heterocycles under aero-
bic conditions.
plore additional conditions. Numerous other solvents
were tested (acetonitrile, dichloroethane, dimethylacet-
amide, dimethoxyethane, dimethylformamide, dioxane,
nitromethane, and toluene), and ∼40% yields of 2a were
obtained in acetonitrile and toluene (entries 3 and 4).
Replacement of NaOBz with other bases (e.g., NaOAc,
The challenge of preparing six-membered rings via
Wacker-type oxidative cyclization is illustrated with sub-
strate 1a, a precursor to 3-vinylmorpholine derivative 2a
(Scheme 1). Cyclization of this substrate was attempted with
two of the most versatile catalyst systems that have been
reported previously: Pd(OAc)2 in DMSO as the solvent,
introduced by Larock and Hiemstra,9 and Pd(OAc)2/pyridine
in toluene, which we reported in 2002.10ꢀ12 These catalysts
have been used to prepare diverse pyrrolidine derivatives, but
they have exhibited limited success in the preparation of six-
membered rings. Reactions of 1a with these catalysts afforded
only trace yields of product 2a (Scheme 1).
Scheme 1. Illustration of the Difficulty of Wacker-Type
Cyclization To Afford a Six-Membered Heterocycle
We recently identified Pd(DMSO)2(TFA)2 as an effec-
tive catalyst for the oxidative cyclization of allylic sulfa-
mides in THF.7b Use of DMSO as a stoichiometric ligand
for the Pd catalyst in 2:1 stoichiometry, rather than the
solvent, resulted in a significantly higher product yield, and
optimal results were obtained with sodium benzoate
(NaOBz) as a Brønsted base. We tested similar catalytic
conditions for the cyclization of 1a. A 15% yield of 2a
was obtained when 10 mol % Pd(DMSO)2(TFA)2 was
used as the catalyst in THF with 1 equiv of NaOBz
(Table 1, entry 1), an outcome slightly better than that
observed with DMSO as the solvent (entry 2). Despite the
modest yields from these reactions, the improvements
relative to the results in Scheme 1 prompted us to ex-
Table 1. Evaluation of Catalytic Conditions for Intermolecular
Oxidative Amination of Alkenesa
mol %
PdII
entry
solvent
comment
(conv) yieldb
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
5
THF
1 equiv NaOBz
1 equiv NaOBz
1 equiv NaOBz
1 equiv NaOBz
no base
(43) 15
(35) 10
(70) 41
(68) 38
(80) 57
(100) 62
(50) 32
(51) 31
(100) 71
DMSO
MeCN
toluene
MeCN
toluene
toluene
toluene
toluene
(6) Pd-catalyzed carbopalladation of alkenes provides an alternate
route to six-membered N-heterocycles. For representative examples, see
the following: (a) Bowie, A. L., Jr.; Trauner, D. J. Org. Chem. 2009, 74,
1581–1586. (b) Yip, K.-T.; Li, J.-H.; Lee, O.-Y.; Yang, D. Org. Lett.
2005, 7, 5717–5719. (c) Baran, P. S.; Corey, E. J. J. Am. Chem. Soc. 2002,
124, 7904–7905.
no base
c
Pd(OAc)2
no base
d
5
no base, 60 psi O2
(7) For applications of this catalyst system to other Pd-catalyzed aerobic
oxidation reactions, see the following: (a) Brasche, G.; Garcıa-Fortanet, J.;
Buchwald, S. L. Org. Lett. 2008, 10, 2207–2210. (b) McDonald, R. I.; Stahl,
S. S. Angew. Chem., Int. Ed. 2010, 49, 5529–5532. (c) Diao, T.; Stahl, S. S.
J. Am. Chem. Soc. 2011, 133, 14566–14569.
(8) This catalyst system is typically prepared in situ from Pd(TFA)2
and 2 equiv of DMSO. The “Pd(DMSO)2(TFA)2” notation is used to
distinguish this catalyst composition from the common Pd(O2CR)2/
DMSO catalysts that employ DMSO as the solvent. 1H NMR and IR
spectroscopic studies demonstrate that Pd(DMSO)2(TFA)2 is the cata-
lyst composition formed in situ (see ref 7b). For crystallographic
characterization of trans-Pd(DMSO)2(TFA)2, see: Bancroft, D. P.;
Cotton, F. A.; Verbruggen, M. Acta Crystallogr., Sect. C 1989, 45,
1289–1292.
(9) See ref 5b and the following: (a) Larock, R. C.; Hightower, T. R.
J. Org. Chem. 1993, 58, 5298–5300. (b) van Benthem, R. A. T. M.;
Hiemstra, H.; Michels, J. J.; Speckamp, W. N. J. Chem. Soc., Chem.
Commun. 1994, 357–359.
(10) Fix, S. R.; Brice, J. L.; Stahl., S. S. Angew. Chem., Int. Ed. 2002,
41, 164–166.
(11) The Pd(OAc)2/pyridine catalyst system was first reported for
aerobic alcohol oxidation: Nishimura, T.; Onoue, T.; Ohe, K.; Uemura,
S. J. Org. Chem. 1999, 64, 6750–6755.
(12) For other examples of oxidative cyclization reactions catalyzed
by a PdX2/pyridine catalyst systems (X = carboxylate), see: (a)
Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578–
9579. (b) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem.
Soc. 2005, 127, 17778–17788. (c) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu,
N.-Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130–3131.
a Conditions: 1a (0.075 mmol), Pd(TFA)2 (5 or 10 mol %), DMSO
(10 or 20 mol %), base, solvent (0.1 M), 3A MS (20 mg), O2 (1 atm),
60 °C, 13 h. b Conversion of 1a in parentheses; yield determined by 1H
NMR spectroscopy with 1,3,5-trimethylbenzene as the int. std. c Pd-
(OAc)2 used instead of Pd(TFA)2. d Substrate concentration of 0.032 M.
NaHCO3, and Na2CO3) did not have a significant impact
on the outcome of the reaction, but the yield improved to
∼60% in the absence of added base (entries 5 and 6).
Replacing Pd(TFA)2 with Pd(OAc)2 as a catalyst precur-
sor led to a lower yield of 2a (32%, entry 7).
The yield of 2a decreased significantly upon reducing the
catalyst loading from 10 to5 mol % (entry 8). The presence
of Pd black at the end of the reaction suggested that the low
conversion under these conditions could be explained,
at least in part, by decomposition of the catalyst. The
yield of 2a increased to 71% when the reaction was
performed under 60 psi of O2. We have previously noted
(13) Rogers, M. M.; Kotov, V.; Chatwichien, J.; Stahl, S. S. Org.
Lett. 2007, 9, 4331–4334.
Org. Lett., Vol. 14, No. 5, 2012
1235

in intermolecular oxidative oxidative amination reactions
that catalyst stability can be increased under elevated O2
pressures.13 The beneficial effect of the higher O2 pressure
is rationalized by the mechanism in Scheme 2, whereby
productive oxidation of the catalyst (kox step) can be
enhanced relative to catalyst decomposition (kdec step).
Table 2. Pd-Catalyzed Intramolecular Aerobic Oxidative
Amination Reactiona
Scheme 2. Proposed Mechanism of Palladium-Catalyzed
Intramolecular Aerobic Oxidative Amination of Alkenes
The optimized oxidative amination conditions were ex-
amined with a number of different alkene substrates bearing
tethered sulfonamides (Table 2). The reactions were per-
formed at a 0.3 mmol scale under 60 psi of O2 in a Parr
pressure vessel. A higher yield of 2a was obtained (76%
isolated yield) relative to the smaller-scale screening reaction,
and the o-nitrobenzenesulfonamide (Ns) derivative 1b and the
cis-alkene substrate cis-1a also reacted in good yields (86% in
both cases). The trisubstituted alkene derivative 1c reacted to
afford a product with a quaternary carbon center adjacent to
nitrogen (entry 4, 73% yield), and the reaction of the sub-
strates with branching at the carbon centers on either side of
the oxygen atom, 1dꢀ1g, afforded the desired products with
good diastereoselectivities (entries 5ꢀ8). N-Tosyl benzomor-
pholine derivatives 2h and 2i formed in near-quantitative yield
from 1h and 1i, respectively (entries 9 and 10).
The reaction of 1j with a terminal alkene led to product 2j,
which probably forms via isomerization of the double bond
of an initial product 2j0 containing an exomethylene substi-
tuent. Alkene isomerization could be mediated by a PdIIꢀH
intermediate (cf. Scheme 2).14 A five-membered cyclic aminal
3j, isolated from this reaction in low yield, formally reflects an
allylic amination product. However, in light of the alkene
isomerization evident in the formation of 2j, this product
probably arises from PdIIꢀH mediated migration of the
double bond of 1j to afford a vinyl ether derivative, followed
by Wacker-type oxidative cyclization of the isomeric sub-
strate (see below for further mechanistic analysis).
a Conditions: 1 (0.3 mmol), Pd(TFA)2 (5 mol %), DMSO (10 mol %),
toluene(0.032 M), 3AMS (80 mg), O2 (60 psi), 60°C, 24h. b Isolated yield.
c E/Z= 2/1. d E/Z = 6/1. e E/Z = 4/1. f Reaction conditions:Pd(DMSO)-
(TFA)2 (15 mol %), [1n] = 0.01 M.
The same catalyst and reaction conditions were applied
to the preparation of other heterocyclic rings, including
piperidine, piperazine, piperazinone, and seven-membered
heterocycles 2kꢀ2n (entries 12ꢀ15). These products were
formed in good yield, although formation of the seven-
membered heterocycle 2n in good yield required the use of
an elevated catalyst loading (15 mol %).
(14) Alkene isomerization in reactions that proceed via PdIIꢀH
intermediates is quite common. For a leading reference, see: Cabri,
W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7.
1236
Org. Lett., Vol. 14, No. 5, 2012

The predominant formation of allylic amide products,
including the formation of 3j from 1j, raises the possibility
that these reactions could proceed via an allylic CꢀH
activation pathway, rather than via aminopalladation of
the alkene (Scheme 3). The allylic amination reactions
reported by White et al., which employ PdII catalysts in
DMSO, are of particular relevance in this context.15 To
distinguish between the two mechanisms, the homoallyl
ether substrate 1o was subjected to the oxidative cycliza-
tion conditions (eq 1), and the reaction mixture was
analyzed by 1H NMR spectroscopy. The seven-membered
ring 2o, expected from an aminopalladation pathway, was
the major product of the reaction. Only a small amount of
the allylic CꢀH activation product 2a was detected; how-
ever, the formation of this product probably arises from
aminopalladation of 1a, which forms in situ via isomeriza-
tion of 1o. Collectively, these observations suggest that
product formation arises predominantly from the amino-
palladation pathway.
mixture remains outside of flammability limits for the
solvent.16 Such conditions were implemented in a 1 g scale
oxidative cyclization of 1i, which was featured in the
five-step synthesis of the unprotected benzomorpholine
product from commercially available starting materials
(Scheme 4). The aerobic oxidative cyclization step
proceeds in quantitative yield under these modified
conditions.
Scheme 4. Gram-Scale Oxidative Cyclization Reaction Using
Diluted O2
Scheme 3. Possible Mechanisms for the Formation of Allylic
Sulfonamide Products
Recent studies have shown that Pd(DMSO)2(TFA)2 is
an important variant of previously known PdII catalyst
systems for aerobic oxidation reactions.7 Its utility has
been demonstrated for diverse methods, including directed
oxidative arylation of CꢀH bonds,7a oxidative heterocy-
clization reactions of alkenes,7b and R,β-dehydrogenation
of cyclic ketones.7c The results presented here show that
Wacker-type aerobic oxidative cyclization reactions can
provide efficient access to six-membered nitrogen hetero-
cycles, and the Pd(DMSO)2(TFA)2 catalyst system is
critical to the success of these reactions.
Acknowledgment. We are grateful to Dr. Charlie Fry
(UW-Madison) for assistance in NMR characterization of
heterocyclic products. We thank the NIH (R01 GM67173)
for financial support of this work and Eli Lilly and
Johnson-Matthey for generous donations of Pd salts.
Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The use of high pressures of O2 with an organic solvent is
a potential safety hazard. This issue can be addressed by
diluting the O2 with an inert gas, such as N2, to ensure the
(16) (a) Laut, P. B.; Johnstone, D. Chem. Eng. (New York) 1994, 101,
96–104. (b) Ye, X.; Johnson, M. D.; Diao, T.; Yates, M. H.; Stahl, S. S.
Green Chem. 2010, 12, 1180–1186.
(15) (a) Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346–
1347. (b) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C.
J. Am. Chem. Soc. 2005, 127, 6970–6971. (c) Fraunhoffer, K. J.; White,
M. C. J. Am. Chem. Soc. 2007, 129, 7274–7276.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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