The tandem Heck-allylic substitution reaction: a novel route to lactams.

Article abstract of DOI:10.1021/ol027169x

[reaction: see text] A novel route to substituted lactams has been developed using a tandem Heck-allylic substitution reaction. The palladium-catalyzed reaction between omega-olefinic N-tosyl amides and vinylic bromides affords in one step the substituted

Full text of DOI:10.1021/ol027169x

ORGANIC
LETTERS
2003
Vol. 5, No. 3
259-261
The Tandem Heck−Allylic Substitution
Reaction: A Novel Route to Lactams
Pedro Pinho, Adriaan J. Minnaard,* and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute,
UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
Minnaard@chem.rug.nl
Received October 25, 2002
ABSTRACT
A novel route to substituted lactams has been developed using a tandem Heck−allylic substitution reaction. The palladium-catalyzed reaction
between ω-olefinic N-tosyl amides and vinylic bromides affords in one step the substituted pyrrolidones and piperidones in 49−82% isolated
yield. In addition, it is shown that an N-phenyl amide can act as a nucleophile in intramolecular allylic substitution reactions.
Palladium-catalyzed tandem reactions have enjoyed consid-
erable interest during the past decade.1 Several combinations
of reactions have been developed both to prepare complex
natural products2 and to provide direct entry into synthetic
building blocks.
The observation that the palladium-catalyzed reaction
between a vinyl halide and an unactivated olefin often results
in the formation of a stable π-allylpalladium species has led
to the development of the tandem Heck-allylic substitution
reaction.3 This reaction, elaborated upon extensively by
Larock and co-workers,4 has been carried out in an intramo-
lecular version,5 as a two-component coupling (either in the
Heck reaction step6 or in the allylic substitution5c), or as a
three-component coupling.1a,5c,7 Carbon,5c,8 oxygen,9 and
nitrogen10 nucleophiles have been used. In one particular
study, an intermolecular Heck reaction followed by an
intramolecular allylic substitution was used to prepare a
variety of N-tosyl 2-(1-alkenyl)pyrrolidines and -piperidines
starting from acyclic olefinic sulfonamides.6
We were interested in expanding this coupling-cyclization
strategy to acyclic amides to provide the corresponding
lactams. Substituted five-membered and six-membered lac-
tams (pyrrolidones and piperidones) are found in innumerable
natural products and pharmaceutical compounds.11 In addi-
tion, whereas 2-alkyl11 and 2-(2-alkenyl) lactams are readily
available via N-acyliminium ion chemistry,12 the correspond-
ing 2-(1-alkenyl)-lactams are not easily accessible.
* Corresponding authors. E-mail for B.L.F.: Feringa@chem.rug.nl.
(1) (a) Tsuji, J. Palladium Reagents and Catalysts; Wiley: New York,
1995. (b) Malleron, J.-L.; Fiaud, J.-C.; Legros, J.-Y. Handbook of Palladium-
Catalyzed Organic Reactions; Academic Press: London, 1997.
(2) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH:
Weinheim, Germany, 1996; Chapter 31.
Initially, the olefinic amides 1a-c were reacted with
1-bromopropene13 and catalytic palladium acetate using the
(3) (a) Patel, B. A.; Heck, R. F. J. Org. Chem. 1978, 43, 3898. (b) Heck,
R. F. Org. React. 1982, 27, 345.
(4) Larock, R. C.; Tu, C. Tetrahedron 1995, 51, 6635 and references
therein.
(6) Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org. Chem.
1994, 59, 4172.
(7) Xie, X.; Lu, X. Y. Tetrahedron Lett. 1999, 40, 8415.
(8) Larock, R. C.; Lu, Y.; Bain, A. C.; Russell, C. E. J. Org. Chem.
(5) (a) Harris, G. D., Jr.; Herr, R. J.; Weinreb, S. M. J. Org. Chem. 1992,
57, 2528. (b) Harris, G. D., Jr.; Herr, R. J.; Weinreb, S. M. J. Org. Chem.
1993, 58, 5452. (c) Nylund, C. S.; Klopp, J. M.; Weinreb, S. M. Tetrahedron
Lett. 1994, 35, 4287. For an example in which a conjugated diene is used,
see: (d) Overman, L. E. Pure Appl. Chem. 1994, 66, 1423. For an example
in which an allene is used, see: (e) Larock, R. C.; Zenner, J. M. J. Org.
Chem. 1995, 60, 482.
1991, 56, 4589.
(9) Larock, R. C.; Leuck, D. J.; Harrison, L. W. Tetrahedron Lett. 1988,
29, 6399.
(10) For a comprehensive collection of the literature until 1997, see ref
1b.
10.1021/ol027169x CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/11/2003

conditions of Larock et al. (Scheme 1 and Figure 1).6 The
so because a recently described intramolecular aminopalla-
dation of a p-nitrophenyl carbamate met with failure.18
Probably, the pKa difference between an N-phenyl and an
N-benzyl amide (22.4 and 25.8, respectively)19 is sufficient
to allow deprotonation by Na2CO3 in boiling acetonitrile.
For the reaction to succeed, the choice of base and phase-
transfer reagent turned out to be very important. The use of
organic bases such as Et3N or Cy2NMe proved to be
inadequate and led to precipitation of Pd-black within the
first few minutes of heating. Even the combined use of an
organic base with n-Bu4NCl was not successful. Other phase-
transfer reagents such as n-Bu4NBr could be used, but the
reaction was then considerably slower. It appears that the
n-Bu4NCl may have two roles, acting not only as a phase-
transfer reagent but also providing chloride as a stabilizing
ligand for palladium.20
reaction with primary amide 1a14 and N-benzyl amide 1b15
Scheme 1. Tandem Heck Coupling-Allylic Substitution
Reaction of Amides
did not afford any trace of cyclized products, and analysis
of the crude reaction mixture showed only starting material.
This is not unexpected because in the cyclization of sul-
fonamides, the deprotonated species is the nucleophile, while
the less acidic amides may not get deprotonated under these
conditions. Consequently, the neutral amides would not be
sufficiently nucleophilic to attack a π-allylpalladium spe-
cies.16
These promising results encouraged the screening of a
variety of phosphorus ligands. The ligand turned out to be
an important factor in the reaction rate. Shown in Table 1
Table 1. Phosphorus Ligand Effect
reaction time
entry
P liganda
(h)
% conversionb
1
2
3
4
5
6
7
P(OEt)3
P(OPh)3
P[O(p-cyanophenyl)]3
PPh3
P(NMe2)3
P[O(2,6-dimethylphenyl)]3
P(o-tolyl)3
20
16
16
46
24
16
20
54
94
100
97
72
83
92
1
a Metal/ligand ratio ) 1/2. b Determined by H NMR.
are the results obtained with seven different phosphorus
ligands for the conversion of 1c into 2c.21 If the data in this
table are analyzed using a Tolman plot,22 a clear correlation
is observed: ligands with larger cone angles and/or poorer
electron-donating properties gave rise to faster reactions. An
exception is entry 6, although the deviation was found to be
due to the lower stability of this ligand. When a slightly larger
amount of ligand was used, a higher conversion was
obtained.
Figure 1. Tandem Heck coupling-cyclization mechanism.3
However, encouraging results were obtained when N-
phenyl amide 1c was used as a substrate. After 46 h at 90
°C, 97% of the starting material had been converted and 2c
was isolated in 41% yield.17 This is remarkable, all the more
(17) Byproducts could not be identified.
(18) Overman, L. E.; Remarchuk, T. P. J. Am. Chem. Soc. 2002, 124,
12.
(19) Determined in DMF: Maran, F.; Celadon, D.; Severin, M. G.;
Vianello, E. J. Am. Chem. Soc. 1991, 113, 9320.
(11) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int.
Ed. 2000, 39, 625 and references cited therein.
(12) (a) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
2, pp 1047-1082. (b) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron
2000, 56, 3817.
(20) Jeffery, T.; David, M. Tetrahedron Lett. 1998, 39, 5751. Wolf, L.
B.; Tjen, K. C. M. F.; Ten Brink, H. T.; Blaauw, R. H.; Hiemstra, H.;
Schoemaker, H. E.; Rutjes, F. P. J. T. AdV. Synth. Catal. 2002, 1, 70. It
should also be mentioned that it was important to dry the phase-transfer
reagent; see Supporting Information. When commercially supplied n-Bu4-
NCl under otherwise anhydrous conditions was used, the conversion was
about one-third during the same reaction period.
(13) Used as a mixture of isomers. Due to the reaction mechanism, this
leads solely to the trans-substituted product, see ref 6.
(14) This compound was prepared according to the procedure by: Knapp,
S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006.
(21) P[O(p-Cyanophenyl)]3 was prepared according to the procedure
reported by: Iselin, B.; Rittel, W.; Sieber, P.; Schwyzer, R. HelV. Chim.
Acta 1957, 40, 373. P[O(2,6-Dimethylphenyl)]3 was prepared according to
the procedure reported by: Burton, S. D.; Kumara Swamy, K. C.; Holmes,
J. M.; Day, R. O.; Holmes, R. R. J. Am. Chem. Soc. 1990, 112, 6104.
(22) (a) Tolman, C. A. Chem. ReV. 1977, 77, 313. (b) Crabtree, R. H.
The Organometallic Chemistry of the Transition Metals, 2nd ed.; Wiley &
Sons: New York, 1994; Chapter 4, p 85.
(15) This compound was prepared according to the procedure by:
Marson, C. M.; Grabowska, U.; Fallah, A. J. Org. Chem. 1994, 59, 291.
(16) Amides, however, act as nucleophiles in the aminopalladation of a
double bond. The addition of a deprotonated amide to a π-allyl palladium
intermediate is known; see: Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui, S.;
Shibasaki, M.; Mori, M. J. Org. Chem. 1995, 60, 2016.
260
Org. Lett., Vol. 5, No. 3, 2003

Although the rate of the reaction could be increased by
using phosphite ligands, the isolated yield did not signifi-
cantly increase. On the basis of ligand stability, reaction
times, and conversions, the ligand of choice for these tandem
reactions was P(o-Tolyl)3.23
Table 2. Tandem Products Using Amides 3 and 4
It is evident that an electron-withdrawing group at nitrogen
is important for a successful cyclization. It was therefore
anticipated that the use of N-tosyl amides might overcome
the problems experienced with the N-phenyl amides. The
pKa of an N-tosyl amide is comparable to that of a carboxylic
acid.24 Starting from commercially available carboxylic acids,
the corresponding N-tosyl amides 3 and 4 were prepared
following a literature procedure25 in excellent yield (Scheme
2).26
Scheme 2. Synthesis of N-Tosylamides
Tandem Heck-allylic substitution reactions using 3 and
4 were carried out under similar conditions as for amide 1a-
c. Overnight, both substrates afforded the desired lactams
with a variety of olefinic side chains27 in reasonable to good
isolated yields. The results are summarized in Table 2. As
can be seen from this table, even the use of heavily
substituted vinyl bromides results in the corresponding
pyrrolidones and piperidones.
To illustrate that the corresponding amides are easily
accessible from products 5 and 6, 5a was desulfonylated by
treatment with sodium naphthalenide in DME28 to afford the
corresponding amide 7 in 79% yield (Scheme 3).29
products can be easily desulfonylated and are valuable
building blocks for natural product synthesis. In addition, it
has been shown that N-phenyl amides are able to act as
nucleophiles in intramolecular allylic substitution reactions,
a finding that should elicit more research in this field.
Acknowledgment. The authors thank DSM for financial
support.
Supporting Information Available: Experimental details
describing the synthesis and characterization of 2c, 3, 4, 5a-
d, 6a-d, and 7. This material is available free of charge via
the Internet at http://pubs.acs.org.
Scheme 3. Desulfonylation of 5a
OL027169X
(25) Feldman, K. S.; Bruendl, M. M.; Schildknegt, K.; Bohnstedt, A. C.
J. Org. Chem. 1996, 61, 5440.
(26) During this research, Overman and Remarchuk reported the in-
tramolecular aminopalladation of an N-tosyl amide in excellent yield and
high ee (ref 18). No details about the synthesis of the substrate were
disclosed.
(27) 1-Bromocyclohex-1-ene was prepared according to the procedure
described by: Billups, W. E.; Lee, G. A.; Arney, B. E.; Whitmire, K. H. J.
Am. Chem. Soc. 1991, 113, 7980.
In conclusion, a new application of the tandem Heck-
allylic substitution reaction has been developed that provides
rapid access to substituted pyrrolidones and piperidones
starting from commercially available carboxylic acids. The
(23) Preparation of the corresponding six-membered ring (piperidone)
required long reaction times, and the reaction never went to completion.
(24) Lei, A.; Lu, X. Org. Lett. 2000, 2, 2699 and references cited therein.
See also: Lei, A.; Liu, G.; Lu, X. J. Org. Chem. 2002, 67, 974.
(28) Greene, T. W.; Wuts, P. G. ProtectiVe Groups in Organic Synthesis,
3rd ed.; Wiley & Sons: New York, 1999.
(29) This compound has been previously prepared using a multistep
route: Vedejs, E.; Meier, G. P. Tetrahedron Lett. 1979, 4185.
Org. Lett., Vol. 5, No. 3, 2003
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