Regioselective palladium-catalyzed formate reduction of N-heterocyclic allylic acetates

Article abstract of DOI:10.1021/jo0624896

The regioselective palladium-catalyzed formate reduction of allylic acetates in five- to eight-membered heterocycles is reported. Reduction of allylic acetates under mild conditions using allylpalladium chloride dimer, phosphines, and formic acid/triethyl

Full text of DOI:10.1021/jo0624896

Recently, Lautens’ group reported palladium-catalyzed for-
mate reduction of allylic carbonates to form terminal olefins
with excellent regio- and diastereoselectivity.5 This reaction was
also used to prepare chiral fluoroalkylated compounds by
Konno’s group.6 We felt that this methodology might also apply
to solve the problem of regioselectivity in modifying the olefins
formed by RCM.7,8 Herein, we would like to report the
palladium-catalyzed formate reduction of allylic acetates of five-
to eight-membered N-heterocycles to transform the endo-olefin
to the exo-position (eq 1).
Regioselective Palladium-Catalyzed Formate
Reduction of N-Heterocyclic Allylic Acetates
Hsiu-Yi Cheng, Chong-Si Sun, and Duen-Ren Hou*
Department of Chemistry, National Central UniVersity,
Jhongli City, Taoyuan, Taiwan 32001
drhou@cc.ncu.edu.tw
ReceiVed December 5, 2006
The synthesis of the required allylic acetates of N-heterocycles
1a-d is shown in Scheme 1. Alkylation of N-(alkenyl)-
tosylamides 2a-d9,10 with 2-bromomethylallyl acetate (3)11
provided the dienes 4a-d for ring-closing metathesis. Grubbs’
catalysts were used to perform the ring formation and gave the
five- to eight-membered allyl acetates 1a-d in good yields.
Palladium-catalyzed formate reductions of 2,5-dihydropyrrole
1a are summarized in Table 1. Trialkylphosphonium salts R3-
PHBF4 were used instead of the air-sensitive trialkylphosphines
to simplify the experimental operations.5,12 Tributylphosphine,
the most frequently used ligand in palladium-catalyzed formate
reductions to generate linear, terminal olefins, was tested first
with some common solvents (entries 1-4). We found that the
effects of the solvents are significant. In THF and CH2Cl2, the
endo-product 6a13 dominates; on the other hand, the desired
exo-product 5a14 is more favored in acetonitrile and DMF.
Therefore, DMF was used in the following studies. Raising the
The regioselective palladium-catalyzed formate reduction of
allylic acetates in five- to eight-membered heterocycles is
reported. Reduction of allylic acetates under mild conditions
using allylpalladium chloride dimer, phosphines, and formic
acid/triethylamine in DMF gives the exo-cyclic olefins in
good regioselectivities and high yields. Synthetic application
in preparing N-tosyl-3-oxo-piperidine is also reported.
Ring-closing metathesis (RCM) has become one of the most
effective methods to form heterocyclic compounds.1 However,
modification of the resulting endo-olefin is limited by the poor
selectivity in discriminating between the two olefinic carbon
atoms. For example, hydroboration and oxymercuration of an
unsymmetrically disubstituted endo-olefin formed by RCM gave
a mixture of regioisomers.2,3 The lack of regioselectivity was
also oberved in epoxidation, followed by nucleophilic ring
opening of endo-olefins.4
(5) (a) Lautens, M.; Paquin, J.-F. Org. Lett. 2003, 5, 3391. (b) Hughes,
G.; Lautens, M.; Wen, C. Org. Lett. 2000, 2, 107. (c) Chau, A.; Paquin,
J.-F.; Lautens, M. J. Org. Chem. 2006, 71, 1924.
(6) Konno, T.; Takehana, T.; Mishima, M.; Ishihara, T. J. Org. Chem.
2006, 71, 3545.
(7) Reviews on palladium-catalyzed formate reduction of allylic com-
pounds: (a) Tsuji, J.; Mandai, T. Synthesis 1996, 1. (b) Tsuji, J.; Minami,
I.; Shimizu, I. Synthesis 1986, 623.
(8) Reported formations of exocyclic olefins by palladium-catalyzed
formate reduction of allylic compounds were limited in carbocycles: (a)
Mandai, T.; Matsumoto, T.; Tsuji, J. Synlett 1993, 113. (b) Tanka, M.;
Mukaiyama, C.; Mitsuhashi, H.; Wakamatsu, T. Tetrahedron Lett. 1992,
33, 4165.
(9) Preparation of homoallyl amine: Abd El Samii, Z. K. M.; Al
Ashmawy, M. I.; Mellor, J. M. J. Chem. Soc., Perkin Trans. 1 1988, 2517.
4-Pentenyl amine: Bertrand, M. B.; Wolfe, J. P. Tetrahedron 2005, 61,
6447. 5-Hexenyl amine and its tosylate: Clark, A. J.; Campo, F. D.; Deeth,
R. J.; Filik, R. P.; Gatard, S.; Hunt, N. A.; Laste´coue`res, D.; Thomas, G.
H.; Verlhac, J.-B.; Wongtap, H. J. Chem. Soc. Perkin Teans. 2000, 1, 671.
(10) Preparation of N-tosyl allyl amine: Brummond, K. M.; Chen, H.;
Mitasev, B.; Casarez, A. D. Org. Lett. 2004, 6, 2161. N-Tosyl homoallyl
amine: Mizutani, T.; Ukaji, Y.; Inomata, K. Bull. Chem. Soc. Jpn. 2003,
76, 1251. N-Tosyl 4-pentenyl amine: Schlummer, B.; Hartwig, J. F. Org.
Lett. 2002, 4, 1471.
(11) Magnusson, G.; Lindqvist, F. Chem. Commun. 1990, 1080.
(12) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(13) (a) Yao, Q.; Zhang, Y. J. Am. Soc. Chem. 2004, 126, 74. (b) Audic,
N.; Clavier, H.; Mauduit, M.; Guillemin, J. C. J. Am. Soc. Chem. 2003,
125, 9248. All of the endo-olefins 6a-d were prepared independently to
confirm their absorption in NMR spectra; see Supporting Information.
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2002, 4, 2257.
(1) Reviews on applications of RCM: (a) Grubbs, R. H.; Miller, S. J.;
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Int. Ed. Engl. 1995, 34, 1833. (b) Schuster, M.; Blechert, S. Angew. Chem.,
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1998, 54, 4413. (d) Fu¨rstner, A. Top. Organomet. Chem. 1998, 1, 37. (e)
Schrock, R. R. Top. Organomet. Chem. 1998, 1, 1. (f) Schrock, R. R.
Tetrahedron 1999, 55, 8141. (g) Blechert, S. Pure Appl. Chem. 1999, 71,
1393. (h) Wright, D. L. Curr. Org. Chem. 1999, 3, 211. (i) Maier, M. E.
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Chem. 1998, 41, 3563.
10.1021/jo0624896 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/08/2007
2674
J. Org. Chem. 2007, 72, 2674-2677

SCHEME 1. Synthesis of N-Heterocycles with Allylic
Acetates
of π-allylpalladium complexes, even though the optimal ratio
of Pd : P is 1 : 2.18
The palladium-catalyzed formate reductions of tetrahydro-
pyridine 1b are summarized in Table 2. Tributylphosphine
provided exo-olefin 5b19 exclusively at room temperature, but
conversion was low. Attempts to increase the conversion by
raising the temperature to 40 °C reduced the ratio (entry 2). In
contrast to the reactions of 1a, reactions using PCy3 and P(t-
Bu)3 proceeded very poorly (entries 3 and 4). To our surprise,
triphenylphosphine provides excellent regioselectivity, favoring
exo-olefin 5b, despite low conversion (entry 5). The other two
analogs of triphenylphosphine, P(1-naphthyl)3 and P(o-Tol)3,
gave even lower conversions and poor regioselectivity (entries
6-8). On the other hand, di-tert-butyl 2-biphenylphosphine
provided both good regioselectivity (exo 96%) and conversion
(94%, entry 9).
The results using seven- and eight-membered N-heterocycles
1c and 1d as the substrates are summarized in Tables 3 and 4.
The endo-products 6c,d, usually the minor component in the
reactions and inseparable from the exo-products 5c,d, were
synthesized independently (see Supporting Information) to
confirm their identity on 1H NMR spectra. We noticed that the
reaction rates of these medium rings are faster than those of 1a
and 1b, which allow us to perform the reductions at 0 °C. Four
selected phosphine ligands were used to effect the reduction.
For both 1c and 1d, di-tert-butyl 2-biphenylphosphine gave
complete conversion and no endo-product was detected on
500 MHz 1H NMR. This aryl and alkyl mixed phosphine,
instead of P(n-Bu)3, is the choice of ligand for this regioselective
reduction of these cyclic substrates.
Solvents, phosphines, and temperatures are important factors
in our studies of the allylic reductions of N-heterocycles 1a-
d. The different reactivity among 1a-d also indicates that this
reaction is sensitive to the subtle conformational change between
the five- to eight-membered rings.
The selective isomerization that we report here has potential
applications in synthesis. Consider, for example, a preparation
of N-tosyl-3-oxo-piperidine (7, eq 2), an intermediate in the
synthesis of Aloperine and carbolines,20,21 by way of RCM.
Oxidation of the exocyclic alkene by ruthenium(III) chloride
and sodium periodate affords 7 cleanly,22 whereas a preparation
that relies on hydration of an endo-alkene followed by oxidation
would lead to mixtures of ketones.2,3
reaction temperature to 40 °C shortened the reaction time and
gave similar selectivity (81-85% of the exo-olefin 5a, entries
4 and 5). Extending the reaction time did not alter the ratio of
the two olefins, which indicates that the alkenes 5a and 6a are
kinetically stable under the reaction conditions (entry 6).
However, when the reaction temperature was 60 °C, endo-
olefin 6a became the major product, indicating that the
thermodynamically more stable endo-product 6a is favored at
high temperature.15
To achieve better regioselectivity, phosphine ligands with
various electronic and steric properties were screened. Tricy-
clohexylphosphine (PCy3) favors the exo-product 5a in a nearly
9 : 1 ratio at room temperature (entry 8). We also found that
the ratio of palladium to phosphine is important. The amount
of exo-olefin 5a increased as the ratios of PCy3 to Pd increased
from one to two (entries 8, 10, and 11). Although adding more
phosphine (up to 4 equiv) slightly improved the regioselectivity
(91%), the rate of conversion was decreased (entry 12). As seen
in the reactions of P(n-Bu)3, raising the reaction temperature to
40 °C was accompanied by lower selectivity (entry 13).
Increasing the size of ligand to tri-tert-butylphosphine led to a
disappointing conversion and selectivity. Triphenylphosphine
only gave the endo-product 6a (entry 15). The selectivity favored
the exo-olefin 5a as the size of the aryl groups increased to
1-naphthyl and o-tolyl (entries 15-17).16 Interestingly, di-tert-
butyl 2-biphenylphosphine, an aryl, alkyl mixed phosphine,
provided the best regioselectivity (93%) among the phosphine
ligands screened for 1a (entry 18). The structurally similar di-
cyclohexyl 2-biphenylphosphine and di-tert-butyl 2-(2′-meth-
ylbiphenyl)phosphine provided better conversions but lower
regioselectivities (entries 20-21). All the bidentate ligands with
different bite angles gave mediocre selectivities (entries 22-
27).17 The ligand with a labile nitrogen donor affored the better
regioselectivity among these bidentates (entry 27). These results
are consistent with Hayashi’s observation that the use of
monodentate phosphines is essential in asymmetric reductions
In conclusion, palladium-catalyzed formate reductions of
allylic substrates is shown to be an effective method to isomerize
the endocyclic olefin formed by RCM to the exo-position, thus
providing one way to circumvent the problem of regioselectivity
in further modification of the cycloalkenes formed by ring-
(15) (a) Cope, A. C.; Ambros, D.; Ciganek, E.; Howell, C. F.; Jacura,
Z. J. Am. Chem. Soc. 1960, 82, 1750. (b) Schriesheim, A.; Muller, R. J.;
Rowe, C. A., Jr. J. Am. Chem. Soc. 1962, 84, 3164. (c) Maryanoff, B. E.;
Almond, H. R., Jr. J. Org. Chem. 1986, 51, 3295.
(18) (a) Hayashi, T. Acc. Chem. Res. 2000, 33, 354. (b) Hayashi, T.;
Iwamura, H.; Naito, M.; Matsumoto, Y.; Uozumi, Y. J. Am. Chem. Soc.
1994, 116, 775.
(19) Radetich, B.; RajanBabu, T. V. J. Am. Soc. Chem. 1998, 120, 8007.
(20) Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc.
1999, 121, 700.
(21) Engler, T. A.; Wanner, J. J. Org. Chem. 2000, 65, 2444.
(22) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
(16) Tolman, C. A. Chem. ReV. 1977, 77, 313.
(17) Bite angles of dppm, dppe, and dppp: Steffen, W. L.; Palenik, G.
J. Inorg. Chem. 1976, 15, 2432. Bite angles of dppf: Hayashi, T.; Konishi,
M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Horotsu, K. J. Am. Chem. Soc.
1984, 106, 158. Bite angles of xantphos: van Harren, R. J.; Goubitz, K.;
Fraanje, J.; van Strijdonek, G. P. F.; Oevering, H.; Coussens, B.; Reek, J.
N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Inorg. Chem. 2001, 40,
3363.
J. Org. Chem, Vol. 72, No. 7, 2007 2675

TABLE 1. Palladium-Catalyzed Allylic Reduction of 1a
1
a Ratios were determined by 500 MHz H NMR of crude reaction mixtures. b Not detected. c Isolated yield, 68%.
mmol) were added to a solution of allylpalladium chloride dimer
closing metathesis. Further application of this methodology to
natural product synthesis is currently being explored.
(1.2 mg, 3.3 × 10-3 mmol) and di-tert-butyl 2-biphenylphosphine
(3.9 mg, 0.013 mmol) in DMF (200 µL) under an atmosphere of
nitrogen. The solution was stirred at room temperature for
5 min. Acetate 1b (19 mg, 0.063 mmol) in DMF (400 µL) was
added to the solution of the palladium complex. After being stirred
Experimental Section
Procedure for Palladium-Catalyzed Formate Reduction.
Triethylamine (54 µL, 0.39 mmol) and formic acid (7 µL, 0.19
2676 J. Org. Chem., Vol. 72, No. 7, 2007

TABLE 2. Palladium-Catalyzed Allylic Reduction of 1b
TABLE 4. Palladium Catalyzed Allylic Reduction of 1d
a Ratios were determined by 500 MHz 1H NMR of crude reaction
mixtures. b Not detected. c Isolated yield, 80%.
46.3, 31.9, 25.6, 21.5. The spectroscopic data of 5b were consistent
with those reported in literature.18
Preparation of Allylic Acetate 1a. Diolefin 4a (480 mg,
1.48 mmol) and first generation Grubbs’ catalyst (20 mg,
0.03 mmol) in CH2Cl2 (2 mL) were heated to reflux for 2 h. The
solvent was removed under reduced pressure, and the crude product
was purified by column chromatography (SiO2; ethyl acetate/
hexanes, 1:1; Rf 0.52) to give compound 1a (338 mg, 1.14 mmol,
77%). 1H NMR (500 MHz, CDCl3) δ 7.68 (2 H, J ) 8.2 Hz), 7.29
(2 H, J ) 8.0 Hz), 5.58 (1H, s), 4.52 (2H, s), 4.10-4.09 (2H, m),
4.05 (2H, d, J ) 3.8), 2.39 (3H, s), 2.01 (3H, s). 13C NMR
(125 MHz, CDCl3) δ 170.4, 143.6, 134.3, 134.1, 129.8, 127.4,
123.0, 60.2, 54.8, 54.7, 21.5, 20.6. HRMS (FAB): calcd for [M +
H]+ (C14H18O4NS) 296.0957, found 296.0958.
a Ratios were determined by 500 MHz 1H NMR of crude reaction
mixtures. b Not detected. c Isolated yield, 80%
TABLE 3. Palladium Catalyzed Allylic Reduction of 1c
N-Tosyl-3-oxo-piperidine (7). Sodium periodate (35 mg,
0.16 mmol) and ruthenium(III) chloride (1 mg, 12 mol %) were
added to the solution of compound 5b (10 mg, 0.04 mmol) in CCl4
(100 µL), acetonitrile (100 µL), and water (150 µL). After being
stirred at room temperature for 2 h, the reaction mixture was diluted
with water (1 mL), extracted with CH2Cl2 (2 mL × 4), dried over
sodium sulfate, filtered, and concentrated to give the crude product.
The crude ketone was further purified by column chromatography
(SiO2; ethyl acetate/hexanes, 1:1; Rf 0.57) to give pure 7 as a
1
colorless solid (7 mg, 70%). H NMR (500 MHz, CDCl3) δ 7.65
(d, J ) 8.2 Hz, 2H), 7.3 (d, J ) 8.1 Hz, 2H), 3.58 (s, 2H), 3.27 (t,
J ) 5.8 Hz, 2H), 2.43 (s, 3H), 2.35 (t, J ) 6.9, 2H), 2.02-1.99
(m, 2H).20
Acknowledgment. This research was supported by the
National Science Council (NSC 94-2113-M-008-007), Taiwan.
We thank Prof. John C. Gilbert, University of Texas at Austin,
for helpful comments. Thanks are also due to Ms. Ping-Yu Lin
at the Institute of Chemistry, Academia Sinica, and Valuable
Instrument Center in National Central University for obtaining
mass analysis.
a Ratios were determined by 500 MHz 1H NMR of crude reaction
mixtures. b Not detected. c Isolated yield, 81%
at room temperature for 21 h, the reaction mixture was diluted with
CH2Cl2 (20 mL), washed with water (3 mL × 2) and saturated
NaCl(aq) (5 mL), dried over Na2SO4, filtered, and concentrated to
give the crude product. The crude product was analyzed by
500 MHz 1H NMR to determine the ratio of 5b to 6b,23 and further
purified by column chromatography (SiO2; ethyl acetate/hexanes,
1:9; Rf 0.43) to give pure compound 5b (13 mg, 0.05 mmol, 80%).
1H NMR (500 MHz, CDCl3) δ 7.63 (d, J ) 8.1 Hz, 2H), 7.29 (d,
J ) 8.1 Hz, 2H), 4.86 (s, 1H), 4.79 (s, 1H), 3.47 (s, 2H), 3.03 (m,
2H), 2.40 (s, 3H), 2.07 (m, 2H), 1.68-1.60 (m, 2H). 13C NMR
(125 MHz, CDCl3) δ 143.4, 140.5, 133.0, 129.5, 127.7, 111.6, 52.4,
Supporting Information Available: Experimental details for
preparation and detailed spectroscopic data of compounds 1a-d,
4a-d, 5a-d, 6a-d, and 7. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0624896
(23) (a) Michrowska, A.; Gulajski, L.; Grela, K. Chem. Commun. 2006,
841. (b) Chang, M.-Y.; Hsu, R.-T.; Chen, H.-P.; Lin, P.-J. Heterocycles
2006, 68, 1173.
J. Org. Chem, Vol. 72, No. 7, 2007 2677