Palladium-catalyzed asymmetric 6-endo cyclization of dienamides with substituent-driven activation

Article abstract of DOI:10.1021/ol300737t

Chiral 2-piperidinone compounds with various C-6 substituents were successfully synthesized via a Pd-catalyzed asymmetric 6-endo cyclization of dienamides, which were evidently activated by both N-p-toluenesulfonyl and C-3 ester substituents.

Full text of DOI:10.1021/ol300737t

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2326–2329
Palladium-Catalyzed Asymmetric 6-Endo
Cyclization of Dienamides with
Substituent-Driven Activation
Hiroshi Tsuchikawa,*,† Yuya Maekawa, and Shigeo Katsumura*
School of Science and Technology, Kwansei Gakuin University, Gakuen 2-1, Sanda,
Hyogo 669-1337, Japan
h-tsuchi@chem.sci.osaka-u.ac.jp; katsumura@kwansei.ac.jp
Received March 22, 2012
ABSTRACT
Chiral 2-piperidinone compounds with various C-6 substituents were successfully synthesized via a Pd-catalyzed asymmetric 6-endo cyclization
of dienamides, which were evidently activated by both N-p-toluenesulfonyl and C-3 ester substituents.
Nitrogen-containing six-membered heterocycles, such
as pyridine, piperidine, and piperidinone, are often found
as the core structural motif in naturally occurring bioactive
compounds and synthetic drugs.1 Among them, 2-piper-
idinone (δ-lactam) has especially attracted much attention
in the synthetic community, because it can be a versatile
precursor of highly functionalized piperidines.2 Various
synthetic approaches to 2-piperidinones have currently been
developed,3 for example, through the aza-DielsꢀAlder
reaction,3c,d ring closing metathesis,3e,f and metal-catalyzed
CꢀH bond amination.3g,h However, the cyclization of
activated CꢀC bonds with a tethered amide,3a,b which
seems to be the most conventional route, has not been well
documented probably due to the lower nucleophilicity of
the amide nitrogen compared to amines.4 Herein, we report
a Pd-catalyzed 6-endo type cyclization of the dienamide with
the appropriate substituents at the nitrogen atom and the
C-3 position to obtain 2-piperidinones with various C-6
substituents. Moreover, we present its enantioselective var-
iants using the BINAP-Pd complex catalyst, which must
provide a valuable synthon for the multisubstituted chiral
piperidinone and piperidine compounds.
† Department of Chemistry, Graduate School of Science, Osaka Univer-
sity, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
(1) For example: (a) Joule, J. A.; Smith, G.; Mills, K. Heterocyclic
Chemistry, 3rd ed.; Chapman and Hall: London, 1995; pp 72ꢀ119.
(b) Roth, H. J., Kleemann, A., Eds. Pharmaceutical Chemistry, Vol. 1:
Drug Synthesis; John Wiley: New York, 1988. (c) Strunz, G. M.; Findlay,
J. A. The Alkaloids; Brossi, A., Ed.; Academic Press: London, 1985; Vol. 26,
pp 89ꢀ183. (d) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon Press:
New York, 1999; Vol. 13, pp 1ꢀ161.
Over the past 10 years, we have developed efficient
synthetic methods for 2,4-disubstituted pyridine and chiral
piperidine compounds based on rapid 6π-azaelectrocycliza-
tion from 1-azatrienes (Scheme 1).5 This rapid cyclization
(2) (a) Escolano, M.; Amat, M.; Bosch, J. Chem.;Eur. J. 2006, 12,
ꢀ
8198–8207. (b) Agami, C.; Dechoux, L.; Hebbe, S.; Menard, C. 60
(4) Some analogous reactions to give γ-lactams and oxazolidinones
are reported. (a) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz,
B. M. Angew. Chem., Int. Ed. 2003, 42, 2892–2895. (b) Overman, L. E.;
Remarchuk, T. P. J. Am. Chem. Soc. 2002, 124, 12–13. (c) Hayashi, T.;
Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1988, 29, 99–102.
(5) (a) Sakaguchi, T.; Kobayashi, T.; Hatano, S.; Tsuchikawa, H.;
Fukase, K.; Tanaka, K.; Katsumura, S. Chem.;Asian J. 2009, 4, 1573–
1577. (b) Kobayashi, T.; Takeuchi, K.; Miwa, J.; Tsuchikawa, H.;
Katsumura, S. Chem. Commun. 2009, 3363–3365. (c) Kobayashi, T.;
Hatano, S.; Tsuchikawa, H.; Katsumura, S. Tetrahedron Lett. 2008, 49,
4349–4351. (d) Kobayashi, T.; Hasegawa, F.; Tanaka, K.; Katsumura,
S. Org. Lett. 2006, 8, 3813–3816. (e) Tanaka, K.; Mori, H.; Yamamoto,
M.; Katsumura, S. J. Org. Chem. 2001, 66, 3099–3110.
Tetrahedron 2004, 60, 5433–5438. (c) Groaning, M. D.; Meyers, A. I.
Tetrahedron 2000, 56, 9843–9873.
(3) For example: (a) Patil, N. T.; Huo, Z.; Bajracharya, G. B.;
Yamamoto, Y. J. Org. Chem. 2006, 71, 3612–3614. (b) Obika, S.; Yasui,
Y.; Yanada, R.; Takemoto, Y. J. Org. Chem. 2008, 73, 5206–5209. (c) 65
Chen, Z.; Lin, L.; Chen, D.; Li, J.; Liu, X.; Feng, X. Tetrahedron Lett.
2010, 51, 3088–3091. (d) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew.
Chem., Int. Ed. 2006, 45, 4796–4798. (e) Fiorelli, C.; Savoia, D. J. Org.
Chem. 2007, 72, 6022–6028. (f) Lee, J. H.; Shin, S.; Kang, J.; Lee, S.
J. Org. Chem. 2007, 72, 7443–7446. (g) Wasa, M.; Yu, J.-Q. J. Am. Chem.
Soc. 2008, 130, 14058–14059. (h) Inamoto, K.; Saito, T.; Hiroya, K.;
Doi, T. J. Org. Chem. 2010, 75, 3900–3903.
r
10.1021/ol300737t
Published on Web 04/24/2012
2012 American Chemical Society

was realized by the remarkable substituent effect due to the
enhancement of the HOMOꢀLUMO interaction in the
6π-electron system mainly derived from the C-4 ester
substituent,5e and the additional electron withdrawing
group at the nitrogen.5a,c,e
although trifurylphosphine or triphenylphosphine was
added as an additive, the desired piperidinone 1P was
not obtained (entries 2 and 3). However, after changing
dioxane to toluene, surprisingly, the cyclization partly proceeded
to afford the expected 2-piperidinone 1P in 38% yield
(entry 4). Encouraged by this result, we finally found when
the bidentate phosphine ligands {1,2-bis(diphenylphosphino)-
ethane(DPPE),1,3-bis(diphenylphosphino)propane(DPPP),
or 1,4-bis(diphenylphosphino)butane (DPPB)} were used, the
reaction smoothly proceeded to produce the desired piper-
idinone in 85%, 85%, and 75% yields, respectively (entries
5 to 7). Meanwhile, utilizing other catalysts, such as
palladium(II) chloride (entry 8), Lewis acid [Sc(OTf)3,
entry 9] ,or base (1,8-diazabicyclo[5.4.0]undec-7-ene: DBU,
entry 10) induced no cyclization. These results obviously
showed that the combination of Pd2(dba)3 with the biden-
tate phosphine ligands was the best for this cyclization
reaction.
To broaden the utility of this reaction, we next examined
the cyclization with dienamide substrates having various
C-5 substituents (Table 2). As shown in entries 1 to 6, the
established set of conditions in Table 1 was successfully
applied to the substrates with some aryl and heteroaro-
matic substituents to afford the corresponding 2-piperidi-
nones in good yields. Moreover, in the case of acyclic
substituents, such as the methoxymethyl and siloxymethyl
derivatives 7 and 8, cyclic products 7P and 8P were found
to occur in significant yields (entries 7 and 8). These results
have shown that this reaction has a high generality for the
C-5-substituents and is a novel approach for the 2-piper-
idinones with various C-6 substituents. Furthermore, re-
garding this reaction as an amide cyclization, it is, to the
best of our knowledge, an unprecedented example of the
Pd-catalyzed intramolecular 1,6-addition of an amide.8
Since promising results of the catalytic cyclization were
obtained, we next focused on the enantioselective conver-
sion (Scheme 3). Taking into consideration the results
above, chiral bidentate phosphine ligands, such as
(R,R)-1,2-bis[(2-methoxyphenyl)phenylphosphino]ethane
(DIPAMP), (ꢀ)-1,2-bis[(2R,5R)-2,5-dimethylphospholano]-
benzene (Me-DUPHOS), (4R,5R)-trans-4,5-bis[(diphenyl-
phosphino)methyl]-2,2-dimethyl-1,3-dioxalane (DIOP),
(R)-[(5,6),(50,60)-bis(ethylenedioxy)biphenyl-2,20-diyl]bis-
(diphenylphosphine) (SYNPHOS), and (S)-2,20-bis-
(diphenylphosphino)-1,10-binaphthyl (BINAP) were
examined (Scheme 3A). Among them, gratifyingly, all
ligands showed certain enantioselectivities, and especially
those with an axial chirality produced a significant increase
in the enantiomeric excess; SYNPHOS was 68% ee and
BINAP was 76% ee, along with 68% and 78% chemical
yields, respectively. In addition, the enantioselective cycliza-
tion using BINAP exhibited generality at the C5-substituents
Scheme 1. Synthetic Methods for 2,4-Disubstituted Pyridines
and Chiral Piperidines via the Rapid 6π-Azaelectrocyclization
In order to further develop our synthetic methodology
using this “substituent-driven activation”, we next
focused on the more challenging variant, catalytic
6π-azaelectrocyclization.6 Because the difficulty of the
catalytic activation of a simple triene system has already
been known,6c,d we carefully designed and devised the
substrate (Scheme 2). Thus, we expected that the addition
of a catalyst to the dienamide compound with the C-3 ester
and N-p-Ts groups would lead to generation of the acti-
vated 1-azatriene form followed by an immediate aza-
electrocyclization to give the 2-piperidinone compound.
Hence, we envisioned that we could not only realize the
catalytic cyclization with substituent-driven activation but
also develop the novel synthetic strategy for substituted
2-piperidinones. Moreover, utilizing a chiralcatalystmight
lead to the promising enantioselective conversion.
Scheme 2. Strategy for 2-Piperidinone Synthesis via the Cata-
lyzed 6π-Azaelectrocyclization
We first chose 3-ethoxycarbonyl-5-phenyl-N-p-toluene-
sulfonyldienamide 1 as a substrate for the cyclization
(Table1).7 As a catalyst, we selected tris(dibenzylideneacetone)-
dipalladium [Pd2(dba)3] which seemed to have a favorable
affinity to 1-azatriene.5b,d The dienamide 1 and a catalytic
amount of Pd2(dba)3 were stirred at 70 °C in dioxane for
6 h only to give the starting material (entry 1). Next,
(6) There are a few reports about the catalyzed 6π electrocyclization:
(8) The intramolecular 1,6-addition of a carboxylic acid or an amide
€
€
(a) Muller, S.; List, B. Angew. Chem., Int. Ed. 2009, 48, 9975–9978.
was quite rare. See: (a) Gunes, M.; Speicher, A. Tetrahedron 2003, 59,
(b) Maciver, E. E.; Thompson, S.; Smith, M. D. Angew. Chem., Int. Ed.
2009, 48, 9979–9982. (c) Tantillo, D. J. Angew. Chem., Int. Ed. 2009, 48,
31–32. (d) Bishop, L. M.; Barbarow, J. E.; Bergman, R. G.; Trauner, D.
Angew. Chem., Int. Ed. 2008, 47, 8100–8103.
8799–8802. (b) Mali, R. S.; Jagtap, P. G.; Patil, S. R.; Pawar, P. N.
J. Chem. Soc., Chem. Commun. 1992, 883–884. (c) Bellinger, G. C. A.;
Campbell, W. E.; Giles, R. G. F.; Tobias, J. D. J. Chem. Soc., Perkin.
Trans. 1982, 2819–2825. (d) Alexakis, A.; Normant, J. F. Tetrahedron
Lett. 1982, 23, 5151–5154. (e) Deyanov, A. B.; Konshin, M. E. Chem.
Heterocycl. Compd. 2005, 41, 511–514.
(7) For the synthesis of all substrates 1ꢀ8, see the Supporting
Information.
Org. Lett., Vol. 14, No. 9, 2012
2327

Table 1. Screening of Reaction Conditions for Cyclization Using 3-Ethoxycarbonyl-5-phenyl-N-p-toluenesulfonyldienamide 1
catalyst
(equiv)
temp
time
(h)
entry
additive
solvent
(°C)
result
1
2
3
4
5
6
7
8
9
10
Pd2(dba)3 (0.3)
Pd2(dba)3 (0.3)
Pd2(dba)3 (0.2)
Pd2(dba)3 (0.2)
Pd2(dba)3 (0.2)
Pd2(dba)3 (0.2)
Pd2(dba)3 (0.2)
PdCl2 (0.2)
ꢀ
dioxane
dioxane
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
70
100
100
100
100
100
100
100
100
100
6
7
7
1
1
1
1
1
1
1
no reaction
no reaction
no reaction
38
P(2-furyl)3 (1.2)
Ph3P (0.8)
Ph3P (0.8)
DPPE (0.4)
DPPP (0.4)
DPPB (0.4)
ꢀ
85
85
75
no reaction
no reactiona
no reaction
Sc(OTf)3 (0.5)
DBU (2.0)
ꢀ
ꢀ
a Partly decomposed.
Table 2. Cyclization Using 3-Ethoxycarbonyl-N-p-toluene-
sulfonyldienamides with Various C5-Substituents
Scheme 3. (A) Screening of Chiral Ligands for Enantioselective
Cyclization; (B) Generality at the C5-Substituents for the En-
antioselective Cyclization
a Pd2(dba)3 0.15 equiv, additive 0.3 equiv. b Pd2(dba)3 0.2 equiv,
additive 0.4 equiv.
a The reaction condition was moderately optimized {Pd2(dba)3 0.05
equiv, BINAP 0.1 equiv}.
to some extent as shown in Scheme 3B (60ꢀ81% ee for six
examples), which suggested that this 6-endo asymmetric
cyclization could be applied for the multisubstituted chiral
piperidinone synthesis. On the other hand, we confirmed the
substituent effect at the nitrogen atom and the C-3 position
(Scheme 4). As presumed, both the N-benzyl substrate 9 and
the compound 11 having a 4-tert-butyldiphenylsiloxymethyl
at the C-3 position led to no reaction under the established
conditions. These results showed that both the N-p-Ts and
C-3 ester groups would be essential for the cyclization.
Two pathways would be possible, when considering the
mechanism of this reaction. One is the catalytic 6π-aza-
electrocyclization as we have described in Scheme 2.6
Although there is no evidence for the formation of the
2328
Org. Lett., Vol. 14, No. 9, 2012

broadly investigated intramolecular amination,12 the cy-
clization preferentially proceeds in an exo mode. Based on
these results, the formal Pd(0) catalyzed 6-endo cyclization
must be unique. It is difficult to judge which mechanism is
reasonable; however, we believe that this reaction has a
promising perspective.
Scheme 4. Substituent Effect at the Nitrogen Atom and the C-3
Position
In summary, we realized a Pd-catalyzed 6-endo type
cyclization of the dienamide with a bidentate phosphine
ligand. The reaction was clearly accelerated by both N-p-
toluenesulfonyl and C-3 ester substituents, which has been
one of the most notable examples of our “substituent-
driven activation”.13 Moreover, by using the BINAP-Pd
catalyst system, we successfully applied this reaction to the
synthesis of chiral 2-piperidinone compounds with various
C-6 substituents. Further extension of the substrate scope,
improvement of the enantiomeric excess, and mechanistic
investigations are currently ongoing in our laboratory.
azatriene intermediate, the substituent effects described
abovemay supportthismechanism.10 The other possibility
is the Pd(0)-catalyzed intramolecular amidation.11 There
are some reports concerning the amide cyclization to the
unsaturated CꢀC bond using a transition metal catalyst.3a,b,4
However, in almost all the reports, even containing the
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research on Innovative
Areas 22106541 from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
(9) In the case of (S)-BINAP, the absolute configuration of 1P was
determined to be 6S by converting it to the already-known compound;
see the Supporting Information for details.
Supporting Information Available. The experimental
details of reactions and 1H and 13C NMR spectra of the
substrates and products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) The probable role of Pd catalyst in this mechanism is that the
Pd(II) species generated from the oxidative addition of Pd(0) to the
acidic NH might stabilize the transition structure of the intermediary
azatriene by a complexation and result in electrostatic acceleration of the
electrocyclization as suggested for related reactions by Schleyer et al.;
see: Jiao, H.; Schleyer, P. v. R. J. Am. Chem. Soc. 1995, 117, 11529–
11535. We are very interested in the computational experiments related
to its transition state and plan to report the results in detail.
(11) There can be two pathways. One includes the insertion of alkenes
into PdꢀN bonds; for example, see: (a) Ney, J. E.; Wolfe, J. P. J. Am.
Chem. Soc. 2005, 127, 8644–8651. (b) Bertrand, M. B.; Neukom, J. D.;
Wolfe, J. P. J. Org. Chem. 2008, 73, 8851–8860. The other includes the
conjugate addition of Pd(0) affording a π-allyl intermediate; for exam-
ple, see: (c) Custar, D. W.; Le, H.; Morken, J. P. Org. Lett. 2010, 12,
3760–3763. (d) Yuguchi, M.; Tokuda, M.; Orito, K. J. Org. Chem. 2004,
69, 908–914.
(12) For recent selected reviews of intramolecular aminations, see:
€
(a) Chemler, S. R. Org. Biomol. Chem. 2009, 7, 3009–3019. (b) Muller,
115 T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev.
ꢁ
2008, 108, 3795–3892. (c) Minatti, A.; Muniz, K. Chem. Soc. Rev. 2007,
36, 1142–1152.
(13) Quite recently, we also reported the noncatalyst thermal azacy-
clization of N-sulfonyl-2,4-dienamides with a prominent “substituent-
driven activation: Tetrahedron Lett. 2012, 53, 837ꢀ841.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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