Rhenium-catalyzed hydroamidation of unactivated terminal alkynes: Synthesis of (E)-enamides

Article abstract of DOI:10.1021/ol702564e

Reactions of cyclic amides with unactivated terminal alkynes in the presence of a catalytic amount of a rhenium complex provided (E)-enamides in high regio- and stereoselectivity (E:Z = >99:<1).

Full text of DOI:10.1021/ol702564e

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5609-5611
Rhenium-Catalyzed Hydroamidation of
Unactivated Terminal Alkynes:
Synthesis of (E)-Enamides
Salprima Yudha S., Yoichiro Kuninobu,* and Kazuhiko Takai*
DiVision of Chemistry and Biochemistry, Graduate School of Natural Science and
Technology, Okayama UniVersity, Tsushima, Okayama 700-8530, Japan
kuninobu@cc.okayama-u.ac.jp; ktakai@cc.okayama-u.ac.jp
Received October 22, 2007
ABSTRACT
Reactions of cyclic amides with unactivated terminal alkynes in the presence of a catalytic amount of a rhenium complex provided (E)-
enamides in high regio- and stereoselectivity (E:Z >99:<1).
)
Transformations that employ substrates with a readily
available N-H bond to provide access to N-heteroatom-
containing compounds are highly desirable.1 Enamide is one
of the important structures that is often found in natural
products and synthetic drugs.2,3 Therefore, a variety of
methods for its synthesis have emerged. In general, enamides
are accessed via dehydrative condensation between aldehydes
and amides.3 There have been numerous protocols for
synthesizing enamides catalyzed by transition metal com-
plexes, such as isomerization of N-allylamides,4 oxidative
amidation of alkenes,5 coupling reactions of vinylamides with
1,3-butadiene,6 and co-oligomerization of N-vinylamides with
alkynes and alkenes.7 Recently, intermolecular hydroami-
dation of terminal alkynes has received much attention.
Reported catalytic systems are limited to ruthenium
catalysts, and the presence of a ligand is necessary to control
the stereoselectivity.8 Therefore, there still remains a sig-
nificant need for more efficient methods to afford enamides
stereoselectively. Previous work in our laboratory and by
other groups show that rhenium complexes are highly
effective catalysts for C-C bond-forming reactions to afford
useful compounds.9,10 On the other hand, there have only
been a few examples of rhenium catalysts that promote C-N
bond-forming reactions; two studies have reported on rhe-
nium-catalyzed C-N bond-forming reactions via hydroami-
nation of alkynes in intramolecular fashion.11 Direct forma-
tion of a new C-N bond by addition of an amine or amide
to a C-C triple bond could be of great significance. We
(7) Tsujita, H.; Ura, Y.; Matsuki, S.; Wada, K.; Mitsudo, T.; Kondo, T.
Angew. Chem., Int. Ed. 2007, 46, 5160-5163.
(8) (a) Goossen, L. J.; Rauhaus, J. E.;. Deng, G. Angew. Chem., Int. Ed.
2005, 44, 4042-4045. (b) Kondo, T.; Tanaka, A.; Kotachi, S.; Watanabe,
Y. J. Chem. Soc., Chem. Commun. 1995, 413-414.
(9) (a) Kuninobu, Y.; Nishina, Y.; Shouho, M.; Takai, K. Angew. Chem.,
Int. Ed. 2006, 45, 2766-2768. (b) Kuninobu, Y.; Tokunaga, Y.; Kawata,
A.; Takai, K. J. Am. Chem. Soc. 2006, 128, 202-209. (c) Kuninobu, Y.;
Nishina, Y.; Nakagawa, C.; Takai, K. J. Am. Chem. Soc. 2006, 128, 12376-
12377. (d) Kuninobu, Y.; Nishina, Y.; Takai, K. Org. Lett. 2006, 8, 2891-
2893. (e) Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc, 2005,
127, 13498-13499.
(10) For recent review see: Hua, R.; Jiang, J.-L. Curr. Org. Synth. 2007,
4, 151-174.
(11) For rhenium-catalyzed intramolecular hydroamination reactions,
see: (a) Ouh, L. L.; Muller, T. E.; Yan, Y. K. J. Organomet. Chem. 2005,
690, 3774-3782. (b) Muller, T. E.; Grosche, M.; Herdtweck. E.; Pleier,
A.-K.; Walter, E.; Yan, Y.-K. Organometallics 2000, 19, 170-183.
(1) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079-
3159.
(2) Yet, L. Chem. ReV. 2003, 103, 4283-4306.
(3) For a recent example, see: Liu, J.; Swidorski, J. J.; Peters, S. D.;
Hsung, R. P. J. Org. Chem. 2005, 70, 3898-3902.
(4) (a) Krompiec, S.; Pigulla, M.; Krompiec, M.; Baj, S.; Mrowiec-Bialon,
J.; Kasperczyk, J. Tetrahedron Lett. 2004, 45, 5257-5261 and references
therein. (b) Stille, J. K.; Becker, Y. J. Org. Chem. 1980, 45, 2139-2145.
(5) (a) Timokhin, V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 17888-
17893. (b) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S.-I.
Tetrahedron Lett. 1992, 33, 6643-6646.
(6) Catellani, M.; Chiusoli, G. P.; Costa, M. J. Organomet. Chem. 1995,
500, 69-80.
10.1021/ol702564e CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/22/2007

report herein the development of regio- and stereoselective
hydroamidation of alkynes to afford enamides.
Preliminary studies were carried out by reaction between
pyrrolidinone (1a) and 1-heptyne (2a) using a series of
rhenium and manganase catalysts (5 mol %). The results are
summarized in Table 1. Initially, the reaction was carried
Table 2. Hydroamidation Reactions of Cyclic Amides with
Alkynesa
Table 1. Transition-Metal-Catalyzed Synthesis of 3aa
entry
catalyst
mol %
yield (%)b
1
2
3
4
5
6
7
[ReBr(CO)3(thf)]2
ReBr(CO)5
Re2(CO)10
5
10
5
2.5
5
15
19
80
58
20
0
Re2(CO)10
Re2(CO)10
c
MnBr(CO)5
Mn2(CO)10
10
6
0
a 1a (1 equiv), 2a (2 equiv). b Isolated yield. c 1,4-Dioxane was used as
a solvent.
out using the [ReBr(CO)3(thf)]2 catalyst that was used for
the C-C bond-forming reactions (entry 1).9 Fortunately, the
catalyst was also suitable for C-N bond-forming reactions
to afford an anti-Markovnikov adduct in 15% yield, and only
the E-isomer was formed at the end of the reaction. After
examination of several rhenium and manganese complexes,
we found that a commercially available rhenium complex,
Re2(CO)10, was active without an additive and could catalyze
the C-N bond formation to afford enamide 3a in 80% yield
and high stereoselectivity (entry 3). The yield of 3a decreased
when the amount of catalyst was reduced to 2.5 mol % (entry
4). Manganese complexes were ineffective for this transfor-
mation (entries 6 and 7).12
To elucidate the generality of this reaction, we next
examined several alkynes and amides. Representative results
are summarized in Table 2. The reaction of tert-butyl
acetylene (2b) proceeded smoothly to afford the correspond-
ing product 3b in 71% yield (entry 1). Upon treatment with
3-phenyl-1-propyne (2c), the pyrrolidinone 1a gave enamide
3c in 77% yield (entry 2). When pyrrolidinone (1a) was
treated with 2d and 2e, the corresponding enamides were
obtained in 70% and 62% yields, respectively (entries 3 and
4).13 These results show that carbonyl groups did not inhibit
the reactions. By employing a larger-sized cyclic amide such
as piperidinone (1b) as a substrate, the reaction with 2a and
2c proceeded sluggishly to give enamides 3f and 3g in 35%
a 1 (1 equiv), 2 (2 equiv). b Isolated yield. c E:Z ) 2:1
and 20% yields, respectively (entries 5 and 6). When the
reaction of azetidinone (1c) with 1-heptyne (2a) was
conducted under the same conditions, a mixture of products
was obtained (E:Z ) 2:1) in 68% yield (entry 7).
Several experiments were carried out to obtain information
on the product selectivity. First, we examined the E-isomer
product 3a by treatment of 1a with 2a under the present
conditions but varying the reaction time (2, 4, 6, 8, 10, 12,
24, and 30 h). Interestingly, in all cases the reaction
proceeded highly selectively to give only the E-isomer
product. On the other hand, when a mixture of isomers 3a′
(E:Z ) 63:37)14 was heated at reflux in toluene in the
presence of Re2(CO)10 (5 mol %); the ratio changed to E:Z
) 70:30 after 12 h. The ratio changed to E:Z ) 100:0 after
72 h (eq 1). This result shows that the rhenium complex
also catalyzed the isomerization of the Z-isomer of 3a to an
E-enamide; however, the rate of the isomerization was slow.
The above two investigations suggest that the present reaction
proceeds in an E-stereoselective manner.
(12) For our recent example of manganese catalytic reaction, see:
Kuninobu, Y.; Nishina, Y.; Takeuchi, K.; Takai, K. Angew. Chem., Int.
Ed. 2007, 46, 6518-6520 and refererences therein.
(13) When phenylacetylene was used as the reaction partner instead of
aliphatic acetylenes, a dimerization reaction of phenylacetylene occurred
giving (E)-1,4-diphenylbut-1-en-3-yne in 45% yield. On the other hand,
when acyclic amides were used instead of cyclic amide, the reaction did
not occur and the amide was recovered almost quantitatively.
(14) The substrate was synthesized following the procedure in ref 8a.
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Org. Lett., Vol. 9, No. 26, 2007

In summary, we have succeeded in developing novel
rhenium-catalyzed regio- and stereoselective hydroamidation
reactions to afford enamides in moderate to good yields. To
the best of our knowledge, rhenium complexes have not been
utilized for such intermolecular hydroamidation of alkynes.
This methodology represents a powerful diverse catalytic
system for the constructions of enamides.
Although the mechanism of the reaction remains uncertain,
one possibility is that the reaction proceeds via the activation
of a C-C triple bond by π-coordination of the alkyne moiety
to the metal center.15 Subsequent formation of a rhenium-
vinylidene intermediate 4, followed by intermolecular nu-
cleophilic attack of the amide group to 4, gives 5.16 Reductive
elimination of rhenium from 5 gives enamide and regenerates
the rhenium catalyst (Scheme 1). Another possibility is the
oxidative addition of the amide group followed by the inser-
tion of the alkyne moiety into the rhenium-amide complex.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas (no.
18037049) from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan, and for Young Scientists
(B) (no. 18750088) from Japan Society for the Promotion
of Science (JSPS). We thank Professor Isao Kadota (Depart-
ment of Chemistry, Okayama University, Japan) for acquiring
HR-MS spectra. S.Y.S. also thank JSPS for a postdoctoral
research fellowship.
Supporting Information Available: Experimental de-
1
tails, characterization data, and copies of both H and 13C
Scheme 1. Plausible Mechanism for the Rhenium-Catalyzed
Hydroamidation of Alkynes
NMR spectra of all compounds (3a-3h). This material
is available free of charge via the Internet at http://
pubs.acs.org.
OL702564E
(15) The complexation between compounds containing multiple C-C
bonds with Re2(CO)10 are known; see: (a) Nubel, P. O.; Brown, T. L.
Organometallics 1984, 3, 29-32. (b) Nubel, P. O.; Brown, T. L. J. Am.
Chem. Soc. 1982, 104, 4955-4957.
(16) For examples of rhenium-vinylidene complexes, see: (a) Bianchini,
C.; Mantovani, N.; Marchi, A.; Marvelli, L.; Masi, D.; Peruzzini, M.; Rossi,
R.; Romerosa, A. Organometallics 1999, 18, 4501-4508. (b) Pombeiro,
A. J. L.; Jeffery, J. C.; Pickett, C. J.; Richards, R. L. J. Organomet. Chem.
1984, 277, C7-C10. (c) Wong, A.; Gladysz, J. A. J. Am. Chem. Soc. 1982,
104, 4948-4950.
Org. Lett., Vol. 9, No. 26, 2007
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