Aerobic oxidative cyclization under Pd(II) catalysis: A regioselective approach to heterocycles

Article abstract of DOI:10.1021/ol052529c

(Chemical Equation Presented) An efficient Yb(OTf)₃-promoted palladium-catalyzed oxidative cyclization of γ-heteroalkenyl β-keto amides has been developed. Under simple aerobic condition, a variety of six-, seven-, and eight-membered-ring N- an

Full text of DOI:10.1021/ol052529c

ORGANIC
LETTERS
2005
Vol. 7, No. 25
5717-5719
Aerobic Oxidative Cyclization under
Pd(II) Catalysis: A Regioselective
Approach to Heterocycles
Kai-Tai Yip, Jin-Heng Li, On-Yi Lee, and Dan Yang*
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road,
Hong Kong, P. R. China
yangdan@hku.hk
Received October 19, 2005
ABSTRACT
An efficient Yb(OTf)3-promoted palladium-catalyzed oxidative cyclization of
γ
-heteroalkenyl
â
-keto amides has been developed. Under simple
aerobic condition, a variety of six-, seven-, and eight-membered-ring N- and O-heterocycles were obtained regioselectively in excellent yield.
Six-, seven-, and eight-membered-ring heterocycles are
common structural motifs of many drugs and biologically
active natural products.1 Transition-metal-catalyzed cycliza-
tion methods have been extensively developed for the
synthesis of heterocycles.2 Among them, Pd(II)-catalyzed
oxidative cyclization is considered to be one of the most
effective strategies.3-5 Apart from the oxidative C-X bond
formation, the oxidative C-C bond-forming reactions pro-
vide an alternative approach to access heterocycles. However,
successful examples are rare and the reported approaches
are limited to five- and six-membered-ring heterocycles
only.6-7 Herein, we report our regioselective approach toward
six- to eight-membered-ring N- and O-heterocycle synthesis
via Yb(OTf)3-promoted and Pd(II)-catalyzed oxidative cy-
clization under simple aerobic conditions.
Recently, Widenhoefer and co-workers reported the oxida-
tive cyclization of alkenyl â-diketones and some â-keto esters
to afford cyclohexenones in the presence of catalytic amounts
of PdCl2(MeCN)2 and 2.5 equiv of CuCl2 as the oxidant.7
Since the use of molecular oxygen, instead of traditional
CuCl2 or benzoquinone, as the sole stoichiometric oxidant
has emerged as a cheap, efficient, and environmentally
benign alternative in the reoxidation of Pd(0) to Pd(II)
species,8 we decided to examine the oxidative cyclization
reactions under aerobic condition.
(1) (a) ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F., Eds.; Pergamon: New York, 1996; Vols. 5 and 9.
(b) Handbook of Heterocyclic Chemistry; Katritzky, A. R., Pozharskii, A.
F., Eds.; Pergamon: New York, 1996. (c) Tietze, L. F.; Modi, A. Med.
Res. ReV. 2000, 20, 304.
(2) For general reviews, see: (a) Nakamura, I.; Yamamoto, Y. Chem.
ReV. 2004, 104, 2127. (b) Bates, R. W.; Satcharoen, V. Chem. Soc. ReV.
1996, 96, 635. For ring-closing metathesis, see: (c) Grubbs, R. H. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Semmelhack,
M. F., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 1115. (d) Deiters, A.;
Martin, S. F. Chem. ReV. 2004, 104, 2199. For Fischer carbene reactions,
see: (e) Barluenga, J.; Santamaria, J.; Toma´s, M. Chem. ReV. 2004, 104,
2259. For multicomponent approaches, see: (f) Balme, G.; Bossharth, E.;
Monteiro, N. Eur. J. Org. Chem. 2003, 21, 4101.
(3) For recent reviews of Pd-catalyzed oxidative reactions in heterocycles
synthesis, see: (a) McDaniel, K. F. In ComprehensiVe Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: New York, 1995; Vol. 12. (b) Balme, G.; Bouyssi, D.; Monteiro,
N. In Handbook of Organopalladium Chemistry for Organic Chemistry;
Negishi, E., Ed.; Wiley: New York, 2002; Vol. II, p 2289. (c) Zeni, G.;
Larock, R. C. Chem. ReV. 2004, 104, 2285. (d) Balme, G.; Bossharth, E.;
Monteiro, N. Eur. J. Org. Chem. 2003, 21, 4101.
As the Pd(II)-catalyzed intramolecular hydroalkylations of
alkenyl â-keto amides could be further improved in the
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presence of Yb(OTf)3 (eq 1),9 we utilized Yb(OTf)3 as the
Lewis acid in the heterocycle synthesis. Under the optimized
conditions, the Pd(II)-catalyzed oxidative cyclization of
various N- and O-alkenyl â-keto amides 1a-i proceeded
smoothly to afford the corresponding N- and O-heterocycles
2a-i in excellent yield (Table 1).10 For N-heterocycles, under
2a and 2c were obtained in excellent yield (entries 1 and 4).
Interestingly, even seven- and eight-membered-ring N-
heterocycles 2d and 2e were obtained in 91% and 59%
yields, respectively (entries 5 and 6).11 A comparable yield
of heterocycle 2e resulted when the reaction was scaled up
to over 1 mmol scale (entry 7).
A series of O-heterocycles 2f-i with different substituents
were also obtained in good yield (Table 1, entries 8-13).
Compared to the N-heterocycles, O-heterocycles could be
formed using smaller amounts of Yb(OTf)3. A general trend
is observed relating to the position of substitution. While
the presence of a γ-methyl group showed no obvious effect
on the reaction rate and yield (entry 9 vs 8), the presence of
methyl substituents at the allylic position of the olefin
retarded the reaction, and thus higher catalyst loadings were
used to ensure excellent yields (entries 10-13). The cy-
clization reactions of γ-heteroalkenyl â-keto amides with 1,1-
or 1,2-disubstituted olefinic group were found unsuccessful.
Although a possible mechanism for the palladium-cata-
lyzed oxidative formation of carbocycles has been suggested
by Widenhoefer and co-worker,7 no intramolecular hy-
droalkylation products have been isolated in our heterocycle-
forming reactions, indicating a good selectivity for the
oxidative cyclization pathway over the competing hydroalky-
lation pathway in our reaction system.7a Hence, deuterium-
labeling experiments were conducted to probe the reaction
mechanism in the heterocycle formation.
Table 1. Palladium-Catalyzed Oxidative Cyclization of
γ-Heteroalkenyl Keto Amides (1a-i) in the Presence of
a
Yb(OTf)3
The formation of 2fa from 1fa without measurable
(4) For examples of Pd(II)-catalyzed C-O bond-forming reactions, see:
(a) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2003, 42, 2892. (b) Uozumi, Y.; Kato, K.; Hayashi, T. J.
Am. Chem. Soc. 1997, 119, 5063. (c) Larock, R. C.; Hightower, T. R. J.
Org. Chem. 1993, 58, 5298.
(5) For examples of Pd(II)-catalyzed C-N bond-forming reactions, see:
(a) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002, 41,
164. (b) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P.
J. Org. Chem. 1996, 61, 3584. (c) Hegedus, L. S. Angew. Chem., Int. Ed.
Engl. 1988, 27, 1113.
(6) (a) Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed.
2004, 43, 6144. (b) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003,
125, 9578. (c) Franzen, J.; Backvall, J.-E. J. Am. Chem. Soc. 2003, 125,
6056. (d) Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704.
(7) (a) Liu, C.; Wang, X.; Pei, T.; Widenhoefer, R. A. Chem. Eur. J.
2004, 10, 6343. (b) Pei, T.; Wang, X.; Widenhoefer, R. A. J. Am. Chem.
Soc. 2003, 125, 648.
a Unless otherwise indicated, all reactions were carried out with 1a (0.15
mmol), PdCl2(MeCN)2 (10 mol %), and Yb(OTf)3 (1 equiv) in dry THF
(10 mL) under 1 atm O2. b Based on isolated product. c 30 mol % of
Yb(OTf)3 was used. d 20 mol % of PdCl2(MeCN)2 was added. e 30 mol %
of PdCl2(MeCN)2 was added. f 0.29 mmol of 1e was used. g 1.23 mmol of
1e was used.
the same reaction conditions (30 mol % of Yb(OTf)3 and
10 mol % of PdCl2(MeCN)2), both Ts- and Boc-protected
substrates 1a and 1b gave similar product yields (entries 2
and 3). When a stoichiometric amount of Yb(OTf)3 was used,
(8) Molecular oxygen has been used as the sole oxidant in several
Pd(II)-catalyzed reactions. See: (a) Stahl, S. S. Science 2005, 309, 1824.
(b) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (b) Brink, G.; Arends,
I. W. C. E.; Sheldon, R. A. Science 2000, 287, 1636.
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Org. Lett., Vol. 7, No. 25, 2005

Scheme 1
Pd(II) species from Pd(0) using molecular oxygen as the
D-content loss (eq 2) demonstrates the highly selective â-H
elimination in yielding R,â-unsaturation of 2fa (Scheme 1).
This explains the preference of the oxidative cyclization over
intramolecular hydroalkylative cyclization.7b On the other
hand, the conversion of 1fb into 2fb was accomplished with
a selective D-shift and retention of high D content (eq 3).12
On the basis of our deuterium-labeling experiments, a
plausible mechanism is shown in Scheme 1. Initially,
Yb(OTf)3 serves as a Lewis acid to promote the enol for-
mation of 1fa and enhance the intramolecular attack of
nucleophilic enol toward Pd(II)-activated olefin (step A).9
With a subsequent â-H elimination (step B) and Pd-migration
(step C), intermediate I is formed. Finally, a selective â-H
elimination of I (step D) resulted in product 2fa. The whole
catalytic cycle is completed by the regeneration of active
oxidant (step E).8
In conclusion, we have developed a mild and efficient
method for the synthesis of N- and O-heterocycles through
oxidative formation of the C-C bond using both Yb(OTf)3
and PdCl2(MeCN)2 as catalysts and molecular oxygen as the
terminal oxidant. A variety of six-, seven-, and even eight-
membered-ring N- and O-heterocycles have been obtained
regioselectively in excellent yield. In addition, the current
methodology is selective in yielding oxidative cyclization
product, and this is complementary to the recent example of
carbocycle formation.7 Further investigations to expand the
scope of this Pd(II)-catalyzed aerobic oxidative cyclization
are in progress.
Acknowledgment. This work was supported by The
University of Hong Kong and Hong Kong Research Grants
Council. D.Y. acknowledges the Bristol-Myers Squibb
Foundation for an Unrestricted Grant in Synthetic Organic
Chemistry and the Croucher Foundation for a Croucher
Senior Research Fellowship Award.
(9) Yang, D.; Li, J.-H.; Gao, Q.; Yan, Y.-L. Org. Lett. 2003, 5, 2869.
(10) The condition using a stoichiometric amount of CuCl2 (ref 7) or
benzoquinone as reoxidant was attempted for γ-N- and O-alkenyl â-keto
amides 1. However, the reactions were found messy and no desired
heterocycle was obtained. In contrast to 1a, γ-(N-allyltosylamido) â-keto
ester did not afford desired heterocyclic product under the aerobic condition.
(11) Formation of seven- and eight-membered-rings by Pd catalysis is
rare. For an unusual example, see: Schweizer, S.; Song, Z.-Z.; Meyer, F.
E.; Parsons, P. J.; Meijere, A. Angew. Chem., Int. Ed. 1999, 38, 1452.
(12) We rule out the possibility of the oxidative cyclization of 1
proceeding through a reaction sequence of tandem Wacker oxidation/
Knoevenagel condensation because this would result in a significant loss
of D content. For example, see: Cornell, C. N.; Sigman, M. S. J. Am. Chem.
Soc. 2005, 127, 2796.
Supporting Information Available: Experimental details
for Pd-catalyzed aerobic oxidative cyclization; preparation
of 1 and characterization data of 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL052529C
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