Expeditious approach to 5-aroyl-pyrrolidinones by a novel PIFA-mediated alkyne amidation reaction

Article abstract of DOI:10.1021/ol0510623

(Chemical Equation Presented) A novel metal-free approach to the alkyne amidation reaction is presented. The oxidation of properly substituted amides by the hypervalent iodine reagent PIFA provides the generation of a nitrenium ion that can react intramol

Full text of DOI:10.1021/ol0510623

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3073-3076
Expeditious Approach to
5-Aroyl-pyrrolidinones by a Novel
PIFA-Mediated Alkyne Amidation
Reaction
Sonia Serna, Imanol Tellitu,* Esther Dom´ınguez,* Isabel Moreno, and
Raul SanMart´ın
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa,
Euskal Herriko Unibertsitatea, P.O. Box 644, 48080 Bilbao, Spain
imanol.tellitu@ehu.es
Received May 9, 2005
ABSTRACT
A novel metal-free approach to the alkyne amidation reaction is presented. The oxidation of properly substituted amides by the hypervalent
iodine reagent PIFA provides the generation of a nitrenium ion that can react intramolecularly with a triple bond, leading to the construction
of the title compounds.
The intramolecular addition of nitrogen functionalities across
carbon-carbon multiple bonds is a highly efficient route to
nitrogen-containing heterocycles. Fueled by the development
of new catalyst systems, inter- and intramolecular alkyne
hydroamination is becoming an interesting approach to the
formation of linear or cyclic amines or imines that meets
today’s requirements for atom economy.1 The employment
of alkaline metals,2 transition metal complexes,3 lanthanides,4
and actinides5 as catalysts offers a representative overview
of the research in this area.6 However, the employment of
high quantities of either toxic or expensive metal salts, the
high sensitivity of some of these complexes to air and
moisture, and the low tolerance to different functional groups
are the major drawbacks of this transformation. Therefore,
the application of these protocols to target-oriented synthesis
is still very limited.7 Thus, the development of new protocols
for alkyne amination reactions remains an important goal in
synthetic organic chemistry.
(1) Recent reviews: (a) Pohlki, F.; Doye, S. Chem. Soc. ReV. 2003, 32,
104. (b) Nobis, M.; Driessen-Ho¨lscher, B. Angew. Chem., Int. Ed. 2001,
40, 3983. (c) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675.
(2) (a) Cid, M. M.; Dom´ınguez, D.; Castedo, L.; Va´zquez-Lo´pez, E. M.
Tetrahedron 1999, 55, 5599-5610. (b) Tzalis, D.; Koradin, C.; Knochel,
P. Tetrahedron Lett. 1999, 40, 6193.
(3) Early transition metals: (a) Bystschkov, I.; Doye, S. Eur. J. Org.
Chem. 2003, 935. (b) Ackermann, L.; Bergman, R. G.; Loy, R. N. J. Am.
Chem. Soc. 2003, 125, 11956. (c) Tillack, A.; Garcia Castro I.; Hartung,
C. G.; Beller, M. Angew. Chem., Int. Ed. 2002, 41, 2541. Palladium: (d)
Yamamoto, Y.; Kadota, I.; Lutete, L. M. J. Am. Chem. Soc. 2004, 126,
1622. (e) Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12670.
(f) Jacobi, P. A.; Brielman, H. L.; Hauck, S. I. J. Org. Chem. 1996, 61,
5013. Ruthenium: (g) Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Angew.
Chem., Int. Ed. 1999, 38, 3222. Rhodium: (h) Hartung, C. G.; Tillack, A.;
Trauthwein, H.; Beller, M. J. Org. Chem. 2001, 66, 6339. Silver: (i) Koseki,
Y.; Kusano, S.; Ichi, D.; Yoshida, K.; Nagasaka, T. Tetrahedron 2000, 56,
8855.
(4) (a) Sukwon, H.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673. (b) Li,
Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757. (c) Li, Y.; Marks, T.
J. Organometallics 1996, 15, 3770.
(5) (a) Stubbert, B. D.; Stern, C. L.; Marks, T. J. Organometallics 2003,
22, 4836. (b) Straub, T.; Haskel, A.; Neyround, T. G.; Kapon, M.;
Botoshansky, M.; Eisen, M. S. Organometallics 2001, 20, 5017.
(6) Some electrophilic reagents also promote related processes. See for
example: (a) I2: Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432. (b)
KMnO4: Hayashi, Y.; Shoji, M.; Yamaguchi, S.; Mukaiyama, T.; Yamagu-
chi, J.; Kakeya, H.; Osada, H. Org. Lett. 2003, 5, 2287. (c) IPy2BF4:
Barluenga, J.; Trincado, M.; Rubio, E.; Gonza´lez, J. M. Angew. Chem.,
Int. Ed. 2003, 42, 2406.
10.1021/ol0510623 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/14/2005

Recently, we reported that the action of the hypervalent
iodine reagent8 [phenyliodine(III)bis-trifluoroacetate] (PIFA)
on N-p-methoxyphenyl-4-pentenamides of type 1 (see Scheme
1) can provide the construction of the 5-hydroxymethyl-
pyrrolidinone derivative 2 efficiently.9 The generation of an
acylnitrenium ion A and its subsequent trapping by the olefin
fragment to form, via intermediate B, the final heterocycle
featuring the vicinal hydroxyamino moiety are the essential
key steps of this transformation.
Scheme 2. PIFA-Mediated Alkyne Amidohydroxylation
Scheme 1. PIFA-Mediated Olefin Amidohydroxylation
a Unreacted starting material was recovered. EDC‚HCl: N-(3-
Dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride. HOBt:
1-Hydroxybenzotriazole. PMP: p-Methoxyphenyl.
Finally, the substitution at the terminal position of the triple
bond12 in amide 4 was introduced by a Sonogashira cross-
coupling reaction13 using appropriately substituted iodides
or bromides (RX) in variable yields (32-81%) as shown in
Table 1.
Amide 5a was selected to optimize the cyclization process.
We tested common aprotic solvents such as CH2Cl2 and CH3-
CN (see Scheme 2), concluding that the use of a fluorinated
alcohol such as trifluroethanol as a solvent14 was essential
for an efficient transformation into the corresponding
5-aroylpyrrolidinone 6a. Another related hypervalent iodine
reagent [phenyliodine(III) diacetate] (PIDA) was also tested
with negative results.
One of the primary driving forces of this 5-exo-dig
cyclization reaction is the aptitude of the triple bond to
behave as a nucleophile. Thus, by modifying the nature of
the aryl ring, we attempted to find a direct relationship
between the feasibility of the final cyclization and the
electron density around the triple bond. As expected (see
Table 1), despite of the lack of reactivity of derivatives 5j-l
under a variety of reaction conditions, a series of pyrrolidi-
nones 6a-h were obtained in moderate to good (58-84%)
yields. On the other hand, pyrrolidinone 6i could be obtained
but in a lower (33%) yield as a result of the diminished
donating properties of the halogen atom.
The hypothesis that we will confirm in this Letter can be
stated as follows. If the success of the former cyclization
relies on the intramolecular nucleophilic attack of the olefin
to the deficient nitrogen, we can presume that a similar
behavior would operate starting from the analogous alkynyl-
amides of type 5. By inspection of the related literature, we
found that the formation of paired imines/enamines is the
final destiny of the triple bond in almost all occasions.10
Therefore, we envisaged that the design of a procedure that
could eventually incorporate functionality across both posi-
tions of the triple carbon-carbon bond in one single step
would be more desirable in order to enrich the versatility of
such functional groups as a synthon for a diverse array of
modern synthetic methods.
The required â-alkynylamide precursors 5a-n were
prepared in a two-step sequence, as outlined in Scheme 2.
Amide 4 was synthesized via EDC‚HCl/HOBt11 coupling of
commercially available 4-pentynoic acid (3) with p-anisidine.
(7) Some exceptions: (a) Trost, B. M.; Fandrick, D. R. Org. Lett. 2005,
7, 823. (b) Koseki, Y.; Sato, H.; Watanabe, Y.; Nagasaka, T. Org. Lett.
2002, 4, 885. (c) McGrane, P. L.; Livinghouse, T. J. Org. Chem. 1992, 57,
1323.
Trying to expand the scope of the presented cyclization,
the behavior of other π-extended systems of olefinic nature
was also tested. Thus, enyne amides 5l-n reacted with PIFA
under standard conditions (see Table 1). Thus, while vinyl-
substituted alkynylamide 5l afforded only complex mixtures
of polymeric materials, 5m,n yielded the desired heterocycles
6m,n, respectively, in good yields.
(8) Some selected reviews about hypervalent iodine chemistry: (a) Wirth,
T. Angew. Chem., Int. Ed. 2005, 44, 3656-3665. (b) Wirth, T. Top. Curr.
Chem. 2003, 224, 1. (c) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002,
102, 2523. (d) Koser, G. F. Aldrichim. Acta 2001, 34, 89. (e) Varvoglis, A.
HyperValent Iodine in Organic Synthesis; Academic Press: London,
1997.
(9) Serna, S.; Tellitu, I.; Dom´ınguez, E.; Moreno, I.; SanMart´ın, R.
Tetrahedron 2004, 60, 6533.
(10) Imines/enamines obtained could be further modified in a second
step: (a) Garcia Castro, I.; Tillack, A.; Hartung, C. G.; Beller, M.
Tetrahedron Lett. 2003, 44, 3217. (b) Haak, E.; Bytschkov, I.; Doye, S.
Eur. J. Org. Chem. 2002, 457. (c) Siebeneicher, H.; Doye, S. Eur. J. Org.
Chem. 2002, 1213.
The described transformation can be rationalized as shown
in Scheme 3. We propose that the nitrenium ion C, generated
(11) Sukekatsu, N. Chem. Lett. 1997, 1.
(12) PIFA reacts with terminal alkynes to produce R-hydroxy ketones;
see: Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. Tetrahedron Lett. 1985,
26, 3837.
(13) For a mini account, see: Sonogashira, K. J. Organomet. Chem. 2002,
653, 46.
(14) Be´gue´, J.-P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004, 18.
3074
Org. Lett., Vol. 7, No. 14, 2005

Table 1. 5-Substituted Pyrrolidinones 6 Prepareda
a Standard reaction conditions: 1.5 equiv of PIFA in CF3CH2OH as a solvent (50 mM based on the amide) at 0 °C for 1-3 h. b Reaction carried out at
65 °C. c Bromides were used instead of the corresponding iodides.
by the action of the mild oxidant PIFA on amides 5,15 reacts
intramolecularly with the alkyne residue to form a new inter-
mediate D. Then, this intermediate, which is stabilized as a
linear carbocation by the donating properties of either the aryl
ring or the electron-enriched olefins, is trapped by a free
ligand delivered by PIFA, resulting in the formation of a
nonisolable ester, E. Ultimately, after basic hydrolysis during
workup, the substituted pyrrolidinone skeleton 6 is formed.
substituent could be removed for further manipulations in
the heterocyclic skeleton. In our case, removal of the PMP
group from derivatives 6 using ammonium cerium(IV) nitrate
(CAN)16 rendered nicely the desired derivatives 7a-e
(Scheme 4). It is noteworthy that pyrrolidinone 7a contains
the main framework of the Clausenamide alkaloid.17
Scheme 4. Removal of the PMP Group
Scheme 3. Mechanism for the Alkyne Amidohydroxylation
In conclusion, a novel, straightforward approach to the
intramolecular amidation of alkynes by a PIFA-promoted
cyclization reaction has been described and applied to the
synthesis of 5-substituted pyrrolidinone derivatives in a few
Finally, the suitability of the presented novel strategy for
the pyrrolidine ring formation oriented to the natural product
synthesis would be of higher interest if the required PMP
(15) (a) Falvey, D. E. In ReactiVe Intermediate Chemistry; Moss, R. A.,
Platz, M., Jones, M., Jr., Eds.; John Wiley & Sons: New Jersey, 2004; pp
593. (b) Kikugawa, Y.; Kawase, M. Chem. Lett. 1990, 581.
(16) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982,
47, 2765.
Org. Lett., Vol. 7, No. 14, 2005
3075

steps and good overall yields. The designed synthesis allows
the preparation of electronically tunable alkyne precursors,
and its effect on the reported cyclization has also been
evaluated.
Acknowledgment. Financial support from the University
of the Basque Country (9/UPV 41.310-13656/2001) and the
Spanish Ministry of Science and Technology (CTQ 2004-
03706/BQU) is gratefully acknowledged. S.S. thanks the
Basque Government for a predoctoral scholarship.
(17) This alkaloid was isolated from an aqueous extract of dry leaves of
Chinese folk medicinal Clausena lansium and exhibits a potent hepatopro-
tective and antiamnesiac effect. (a) Yan, Z.; Wang, J.; Tian, W. Tetrahedron
Lett. 2003, 44, 9383. (b) Hartwig, W.; Born, L. J. Org. Chem. 1987, 52,
4352. (c) A close analogue of Clausenamide could be employed for the
treatment of osteoporosis; see: Cook, J. H.; Barzya, J.; Brennan, C.; Lowe,
D.; Wang, Y.; Redman, A.; Scott, W. J.; Wood, J. E. Tetrahedron Lett.
2005, 46, 1525. (d) Efforts to apply our strategy to the synthesis of the
natural product along with a series of related analogues are currently in
progress and will be published elsewhere.
Supporting Information Available: Characterization
data for compounds 4, 5a-n, 6a-i,m,n, and 7a-e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0510623
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Org. Lett., Vol. 7, No. 14, 2005