Regio- and stereoselective synthesis of 2-amino-1,3-diene derivatives by ruthenium-catalyzed coupling of ynamides and ethylene

Article abstract of DOI:10.1021/ol200812y

A ruthenium-catalyzed hydrovinylation-type cross-coupling of ynamides and ethylene proceeds via ruthenacyclopentene to give 2-aminobuta-1,3-diene derivatives in a highly regioselective manner. It was also demonstrated that 2-aminobuta-1,3-diene derivatives reacted with various dienophiles or singlet oxygen to give a cyclic enamide derivative.

Full text of DOI:10.1021/ol200812y

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2718–2721
Regio- and Stereoselective Synthesis of
2-Amino-1,3-diene Derivatives by
Ruthenium-Catalyzed Coupling of
Ynamides and Ethylene
Nozomi Saito,*,† Keiichi Saito,† Motoo Shiro,‡ and Yoshihiro Sato*,†
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan,
and Rigaku Corporation, Akishima, Tokyo 196-8666, Japan
nozomi-s@pharm.hokudai.ac.jp; biyo@pharm.hokudai.ac.jp
Received March 29, 2011
ABSTRACT
A ruthenium-catalyzed hydrovinylation-type cross-coupling of ynamides and ethylene proceeds via ruthenacyclopentene to give 2-aminobuta-1,3-
diene derivatives in a highly regioselective manner. It was also demonstrated that 2-aminobuta-1,3-diene derivatives reacted with various
dienophiles or singlet oxygen to give a cyclic enamide derivative.
Amino-1,3-diene derivatives have been recognized as
versatile units in synthetic organic chemistry, and many
methods for the preparation of amino-1,3-dienes have
been reported.1 Recently, amino-1,3-diene derivatives
were synthesized by the transition-metal-mediated trans-
formation of ynamides.2ꢀ6
With this background, we planned to investigate the
intermolecular coupling of ynamides and ethylene
mediated by a low-valent ruthenium catalystwiththe focus
of introducing a new protocol for the stereoselective
synthesis of amino-1,3-dienes (Scheme 1). Based on our
previous investigations of the intramolecular reaction of
Transition-metal-catalyzed hydrovinylation of alkynes
is an attractive and efficient strategy for the stereoselective
synthesis of 1,3-dienes from the standpoint of atom
economy.7 It is known that several ruthenium complexes
show high catalytic activity for such hydrovinylation-type
direct cross-couplings of alkynes and alkenes.8,9
(3) For most recent examples of the preparation and reactions of
ynamides, see: (a) Gourdet, B.; Lam, H. W. Angew. Chem., Int. Ed. 2010,
49, 8733. (b) Sato, A.; Yorimitsu, H.; Oshima, K. Bull. Korean Chem.
Soc. 2010, 31, 570. (c) Valenta, P.; Carroll, P. J.; Walsh, P. J. J. Am.
Chem. Soc. 2010, 132, 14179. (d) Poloukhtine, A.; Rassadin, V.;
Kuzmin, A.; Popik, V. V. J. Org. Chem. 2010, 75, 5953. (e) Jia, W.;
Jiao, N. Org. Lett. 2010, 12, 2000. (f) Gourdet, B.; Rudkin, M. E.; Lam,
H. W. Org. Lett. 2010, 12, 2554. (g) Banerjee, B.; Litvinov, D. N.; Kang,
J.; Bettale, J. D.; Castle, S. L. Org. Lett. 2010, 12, 2650. (h) Kramer, S.;
€
Madsen, J. L. H.; Rottlander, M.; Skrydstrup, T. Org. Lett. 2010, 12,
† Hokkaido University.
2758. (i) Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12, 3272. (j)
Li, H.; Hsung, R. P.; DeKorver, K. A.; Wei, Y. Org. Lett. 2010, 12, 3780.
(j) Wakamatsu, H.; Takeshita, M. Synlett 2010, 2322. (k) DeKorver,
K. A.; North, T. D.; Hsung, R. P. Synlett 2010, 2397. (l) Grimster, N. P.;
Wilton, D. A. A.; Chan, L. K. M.; Godfrey, C. R. A.; Green, C.; Owen,
D. R.; Gaunt, M. J. Tetrahedron 2010, 66, 6429. (m) Fadel, A.; Legrand,
F.; Evano, G.; Rabasso, N. Adv. Synth. Catal. 2011, 353, 263. (n)
Schotes, C.; Mezzetti, A. Angew. Chem., Int. Ed. 2011, 50, 3072. (o)
Davies, P. W.; Cremonesi, A.; Martin, N. Chem. Commun. 2011, 47, 379.
(p) Mak, X. Y.; Crombie, A. L.; Danheiser, R. J. Org. Chem. 2011, 76,
1852. (q) Shindoh, N.; Takemoto, Y.; Takasu, K. Heterocycles 2011, 82,
1133. (r) Xu, C.-F.; Xu, M.; Jia, Y.-X.; Li, C.-Y. Org. Lett. 2011, 13,
1556. (s) Kramer, S.; Friis, S. D.; Xin, Z.; Odabachian, Y.; Skrydstrup,
T. Org. Lett. 2011, 13, 1750. See also: References 2d and 2e.
‡ Rigaku Corporation.
(1) For reviews on preparations and reactions of amino-1,3-diene
derivatives, see: (a) Petrzilka, M.; Grayson, J. I. Synthesis 1981, 753 and
references cited therein. (b) Campbell, A. L.; Lenz, G. R. Synthesis 1987,
421 and references cited therein.
(2) For reviews on the chemistry of ynamides, see: (a) Zificsak, C. A.;
Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron
2001, 57, 7575. (b) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett
2003, 1379. (c) Hsung, R. P., Ed. In Tetrahedron Symposia-in-Print No.
118, Tetrahedron 2006, 62, 3783. (d) Evano, G.; Coste, A.; Jouvin, K.
Angew. Chem., Int. Ed. 2010, 49, 2840. (e) DeKorver, K. A.; Li, H.;
Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2010, 110, 5064.
r
10.1021/ol200812y
Published on Web 04/21/2011
2011 American Chemical Society

ene-ynes10aꢀd and allene-ynes10e,f catalyzed by Cp*RuCl-
(cod), the oxidative cycloaddition of ynamides 1 and
ethylene 2 to a low-valent ruthenium complex could give
the ruthenacyclopentene I or II. β-Hydride elimination
from I or IIfollowedby reductiveelimination would afford
the corresponding 1-amino-1,3-diene derivative 3 or
2-amino-1,3-diene derivative 4.
cycloaddition of 5a and ethylene to the ruthenium complex
occurred regioselectively to give the ruthenacyclopentene
II. β-Hydride elimination then gave the intermediate II0
from which reductiveelimination proceeded to afford6a in
a regio- and stereoselective manner.11,12
Scheme 2. Ruthenium-Catalyzed Regioselective Coupling of
Ynamide 5a and Ethylene
Scheme 1. Strategy for the Synthesis of Amino-1,3-dienes
Encouraged by these results, the effects of substituents
on the alkyne part or nitrogen atom were investigated
(Table 1). The coupling reactions of ynamides 5b and 5c,
with an aromatic group on the alkyne, were studied with
ethylene (2) and gave the 2-amino-1,3-dienes 6b and 6c,
respectively, in high yield (runs 1 and 2). When ynamides
5dꢀf, bearing an alkyl group on the alkyne moiety, were
reacted with ethylene (2), the desired coupling products
6dꢀf were stereoselectively produced in low to high yield
(runs 3ꢀ5). On the other hand, the ethylene coupling
reaction of the terminal ynamide 5g or the ynamide having
a TMS group on the alkyne part 5h did not proceed and the
starting ynamideswererecovered (runs 6 and 7). Ynamides
with an N-isopropyl group 5i and an N-phenyl group 5j
also reacted with ethylene (2) in the presence of a ruthe-
nium catalyst, giving the corresponding 2-amino-1,3-diene
derivatives 6i and 6j in 48% and 85% yield, respectively
(runs 8 and 9).
To examine the feasibility of this strategy, tosylamide-
derived ynamide 5a was reacted with ethylene (2, 1 atm) in
the presence of Cp*RuCl(cod) (5 mol %) in MeCN. As a
result, the desired 2-amino-1,3-diene derivative 6a was
obtained in 97% yield as a single isomer, whose regio-
and stereochemistries were determined by NOE experi-
ments (Scheme 2). This result indicated that the oxidative
(4) For our approach to regio- and stereoselective synthesis of
enamide derivatives by Ni(0)-catalyzed multicomponent coupling of
ynamide, aldehyde, and silane, see: (a) Saito, N.; Katayama, T.; Sato, Y.
Org. Lett. 2008, 10, 3829. (b) Saito, N.; Katayama, T.; Sato, Y.
Heterocycles. 2011, 82, 1181.
(5) For Pd-catalyzed ene-yne coupling, see: (a) Lindhardt, A. T.;
Mantel, M. L. H.; Skrydstrup, T. Angew. Chem., Int. Ed. 2008, 47, 2668.
For Rh-catalyzed carbozincation of ynamids, see: (b) Gourdet, B.; Lam,
H. W. J. Am. Chem. Soc. 2009, 131, 3802. (c) Gourdet, B.; Rudkin,
M. E.; Watts, C. A.; Lam, H. W. J. Org. Chem. 2009, 74, 7849. (d)
Gourdet, B.; Smith, D. L.; Lam, H. W. Tetrahedron 2010, 66, 6026. For
Ti-mediated reductive coupling of ynamide and simple alkyne, see:(e)
Tanaka, R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5, 67. (f)
Hirano, S.; Fukudome, Y.; Tanaka, R.; Sato, F.; Urabe, H. Tetrahedron
2006, 62, 3896.
(9) Recently, Tanaka reported the rhodium-catalyzed hydrovinyla-
tion-type direct cross-coupling of alkynes and alkenes giving 1,3-dienes
via a rhodacyclopentene intermediate; see: Shibata, Y.; Hirano, M.;
Tanaka, K. Org. Lett. 2008, 10, 2829.
(10) (a) Mori, M.; Saito, N.; Tanaka, D.; Takimoto, M.; Sato, Y.
J. Am. Chem. Soc. 2003, 125, 5606. (b) Mori, M.; Tanaka, D.; Saito, N.;
Sato, Y. Organometallics 2008, 27, 6313. (c) Tanaka, D.; Sato, Y.; Mori,
M. Organometallics 2006, 25, 799. (d) Tanaka, D.; Sato, Y.; Mori, M.
J. Am. Chem. Soc. 2007, 129, 7730. (e) Saito, N.; Tanaka, Y.; Sato, Y.
Organometallics 2009, 28, 669. (f) Saito, N.; Tanaka, Y.; Sato, Y. Org.
Lett. 2009, 11, 4124.
(11) In acetonitrile, a cationic ruthenium species would be generated
from Cp*RuCl(cod) accompanied by dissociation of chloride ligands.
See: Davies, S. G.; McNally, J. P.; Smallridge, A. J. Adv. Organomet.
Chem. 1990, 30, 1. At the ruthenacycle formation stage, the reaction
proceeded as such cationic ruthenium complex would interact with β-
carbon atom of the ynamide which has a partial negative charge (see ref
4a). Consequently, ruthenacyclopentene II would be formed in a
regioselective manner. In this context, when the reaction of 5a and 2
was carried out in the presence of [Cp*Ru(MeCN)3]PF6 (5 mol %) in
MeCN at room temperature, 2-amino-1,3-diene 6a was produced in
63% yield as a single isomer, and no regioisomer of 6a was observed.
(12) Recently Hsung reported the synthesis of 2-amino-1,3-diene
derivatives via isomerization of allenamide; see: (a) Hayashi, R.; Hsung,
R. P.; Feltenberger, J. B.; Lohse, A. G. Org. Lett. 2009, 11, 2125. (a)
Hayashi, R.; Feltenberger, J. B.; Hsung, R. P. Org. Lett. 2010, 12, 1152.
(6) For ruthenium-catalyzed ring-closing metathesis of ene-ynamide
leading to cyclic-1,3-dienmamide, see: (a) Saito, N.; Sato, Y.; Mori, M.
Org. Lett. 2002, 4, 803. (b) Huang, J.; Xiong, H.; Hsung, R. P.;
Rameshkumar, C.; Mulder, J. A.; Grebe, T. P. Org. Lett. 2002, 4,
2417. (c) Mori, M.; Wakamatsu, H.; Saito, N.; Sato, Y.; Narita, R.;
Sato, Y.; Fujita, R. Tetrahedron 2006, 62, 3872. (d) Wakamatsu, H.;
Sakagami, M.; Hanata, M.; Takeshita, M.; Mori, M. Macromol. Symp.
2010, 293, 5.
(7) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259.
(8) For ene-yne coupling via ruthenacyclopentene formation, see: (a)
Mitsudo, T.; Zhang, S.-W.; Nagao, M.; Watanabe, Y. Chem. Commun.
1991, 598. (b) Trost, B. M.; Martos-Redruejo, A. Org. Lett. 2009, 11,
1071. For ene-yne coupling via hydroruthenation of alkynes, see: (c) Yi,
C. S.; Lee, D. W.; Chen, Y. Organometallics 1999, 18, 2043. (d)
Nishimura, T.; Washitake, Y.; Uemura, S. Adv. Synth. Catal. 2007,
349, 2563. For ene-yne coupling via the formation of ruthenium
viynylidene complex, see: (e) Murakami, M.; Ubukata, M.; Ito, Y.
Tetrahedron Lett. 1998, 39, 7361. For ene-yne coupling via CꢀH
activation process, see:(f) Kakiuchi, F.; Uetsuhara, T.; Tanaka, Y.;
Chatani, N.; Murai, S. J. Mol. Catal. A: Chem. 2002, 182ꢀ183, 511. (g)
Neisius, N. M.; Plietker, B. Angew. Chem., Int. Ed. 2009, 48, 5752.
1-Amino-1,3-diene derivatives were synthesized by ruthenium-catalyzed
direct cross-coupling of alkynes and N-vinylamides; see: (h) Tsujita, H.;
Ura, Y.; Matsuki, S.; Wada, K.; Mitsudo, T.; Kondo, T. Angew. Chem.,
Int. Ed. 2007, 46, 5160.
Org. Lett., Vol. 13, No. 10, 2011
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Table 1. Coupling of Tosylamide-Derived Ynamides and
Ethylene
Scheme 3. Coupling of Chiral Ynamides and Ethylene
run
ynamide
time (h)
yield (%)b
1
5b (R1 = Me, R2 = 4-MeO2CC6H4)
5c (R1 = Me, R2 = 4-MeOC6H4)
5d (R1 = Me, R2 = nBu)
5e (R1 = Me, R2 = CH2CH2OTBS)
5f (R1 = Me, R2 = CH2OTBS)
5g (R1 = Me, R2 = H)
5h (R1 = Me, R2 = TMS)
5i (R1 = iPr, R2 = Ph)
5j (R1 = R2 = Ph)
2
3
6b: quant
6c: 99
2
3a
4a
5a
6a
7a
8a
9
19
21
20
21
18
22
4
6d: 80
6e: 88
(Scheme 4). Thus, various alkenes and alkynes were em-
ployed as dienophiles, giving the corresponding cyclic
enamide derivatives 9ꢀ16 in good yields and in a regio-
and stereoselective manner.
6f: 20 (57)
6g: - (45)
6h: - (83)
6i: 48 (23)
6j: 85
a The reaction was carried out at 60 °C. b Values in parentheses are
the yields of recovered ynamide 5.
Scheme 4. DielsꢀAlder Reaction of 6a and 8a with Various
Dienophiles
Next, the coupling reaction using oxazolidinone-derived
ynamides with ethylene was investigated (Table 2). When
ynamides with an aromatic group on the alkyne moiety
7aꢀc were employed for the coupling with ethylene, 2-ami-
no-1,3-diene derivatives 8aꢀc were obtained in high yield in
a stereoselective manner (runs 1ꢀ3). On the other hand, the
reaction of an alkyl-group-substituted ynamide 7d and
ethylene (2) gave the coupling product in low yield (run 4).
Table 2. Coupling of Oxazolidinone-Derived Ynamides and
Ethylene
run
ynamide
7a (R = Ph)
time (h)
yield (%)b
1
2
2
8a: 86
2
7b (R = 4-MeO2CC6H4)
7c (R = 4-MeOC6H4)
7d (R = nBu)
8b: 87
3
4a
2
8c: 92
25
8d: 10 (89)
a The reaction was carried out at 60 °C. b Values in parentheses are
the yields of recovered ynamide 7.
The chiral 2-amino-1,3-diene 6k was applied to a diaster-
eoselective DielsꢀAlder reaction with tetracyanoethene (TC-
NE), and the enamide derivative 17 was obtained as a single
diastereomer (Scheme 5).14 The most stable conforma-
tion of 6k was found by conformational analysis using
Spartan’06 (Wavefunction, Inc., Irvine, CA) with the
MMFF force field, and the structure was depicted as 18.
Based on this result, it was thought that TCNE would
approach the diene part of 6k to avoid steric repulsion
with the camphor ring of 6k, which might control the
stereochemistry of 17.
Furthermore, chiral ynamides 5k derived from Oppol-
zer’s sultam13 and 7e, prepared from L-phenylalanine,
could be applied in the coupling with ethylene (2), and
the corresponding 2-amino-1,3-dienes 6k and 8e were
obtained in optically active form (Scheme 3).
Next, we turned our attention to the utilization of
2-aminobuta-1,3-diene derivatives we had prepared. First,
we investigated the DielsꢀAlder reaction of 6a and 8a
(14) The absolute configuration at the methyne carbon in the cyclo-
hexene ring of 17 was determined by X-ray crystallographic analysis.
Crystallographic data of 17 have been deposited at the Cambridge
Crystallographic Data Center (CCDC 818816).
(13) For reviews on the use of Oppolzer’s sultam as a chiral auxiliary
in asymmetric synthesis, see: (a) Oppolzer, W. Tetrahedron 1987, 43,
1969. (b) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241.
2720
Org. Lett., Vol. 13, No. 10, 2011

Scheme 5. DielsꢀAlder Reaction of 6k and TCNE
Scheme 6. Reaction of 6a and Singlet Oxygen and Transfor-
mations of Endoperoxide 19
by ruthenium-catalyzed regioselective coupling of yna-
mides and ethylene via the formation of a ruthenacyclo-
pentene intermediate. We have also shown that 2-amino-
1,3-dienes are suitable substrates for the preparation of
cyclic enamide derivatives by a DielsꢀAlder reaction or
reaction with singlet oxygen.
Furthermore, the reaction of 6a and singlet oxygen was
examined (Scheme 6). When a solution of 6a in MeOH was
stirred under oxygen gas (1 atm) in the presence of the
catalytic amount of methylene blue for 1 day, the six-
membered endoperoxide 19 was produced in 85% yield.
The endoperoxide was reduced by Al/Hg15a to give bis-allylic
alcohol derivative 20 in 93% yield. On the other hand, when
the endoperoxide 19 was treated with Et3N followed by
TsOH, it gave the 3-aminofuran derivative 21 in high yield.15b
In summary, we have succeeded in developing a new
method for the synthesis of 2-amino-1,3-diene derivatives
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Science Research on Priority Areas (Nos.
19027005 and 20036005, Synergy of Elements) from
MEXT, Japan and a Grant-in-Aid for Scientific Research
(B) (No. 23390001) from JSPS. N.S. acknowledges the
Research Foundation for Pharmaceutical Sciences for
financial support.
Supporting Information Available. Experimental pro-
cedure and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) (a) Pearson, A. J.; Lai, Y.-S.; Srinivasan, K. Aust. J. Chem. 1992,
45, 109. (b) Kondo, K.; Matsumoto, M. Tetrahedron Lett. 1976, 17, 4363.
Org. Lett., Vol. 13, No. 10, 2011
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