Cobalt(III) porphyrin catalyzed aza-Diels-Alder reaction

Article abstract of DOI:10.1021/ol3020946

An efficient protocol for the aza-Diels-Alder reaction of electron-deficient 1,3-dienes with unactivated imines in the presence of a cationic cobalt(III) porphyrin complex was developed. The transformation proceeded smoothly to afford the desired piperidi

Full text of DOI:10.1021/ol3020946

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Cobalt(III) Porphyrin Catalyzed
Aza-DielsꢀAlder Reaction
Ryota Wakabayashi, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoto 615-8510, Japan
kurahashi.takuya.2c@kyoto-u.ac.jp; matsubara.seijiro.2e@kyoto-u.ac.jp
Received July 28, 2012
ABSTRACT
An efficient protocol for the aza-DielsꢀAlder reaction of electron-deficient 1,3-dienes with unactivated imines in the presence of a cationic
cobalt(III) porphyrin complex was developed. The transformation proceeded smoothly to afford the desired piperidine scaffold within 2 h at
ambient temperature. Highly chemoselective cycloaddition of imines with dienes in the presence of a variety of carbonyl compounds was also
demonstrated.
The [4 þ 2] cycloaddition of dienes with imines, namely,
the aza-DielsꢀAlder reaction, is a versatile method for
constructing privileged scaffolds such as the piperidine
scaffold and is hence considered to have potential applica-
tions in the synthesis of natural products and pharmaceu-
ticals. Therefore, the development of [4 þ 2] cycloaddition
strategies involving the use of a catalyst and a mediator
has been a research topic of great interest.1 Many of the
precedent aza-DielsꢀAlder reactions demonstrate high
regioselectivity and enantioselectivity but require the use
of electron-rich and extremely reactive Danishefsky-type
dienes, which severely restricts their widespread applica-
tion in organic synthesis.2 Herein, we report that the aza-
DielsꢀAlder reaction of simple 1,3-dienes, which are less
reactive than Danishefsky dienes, with imines is efficiently
catalyzed by a cationic cobalt-porphyrin complex toafford
piperidines.
of metalloporphyrins can be attributed to their character-
istic structure, in which the tetradentate porphyrin ligand
shows rigid in-plane coordination to the metal. Hence,
we presumed that a hard Co3þ Lewis acid catalyst could
be prepared using a porphyrin ligand and a weakly co-
ordinating axial ligand, so that the cationic nature of Co3þ
is revealed.3 Such a complex would preferentially coordi-
nate with a hard Lewis base such as an imine and chemo-
selectively activate simple dienes, thus compensating for
their low reactivity; consequently, [4 þ 2] cycloaddition
would proceed efficiently to afford the corresponding
piperidines.4 To test our hypothesis, we carried out the
reaction of imine 1a with diene 2a in the presence of
[Co(TPP)]BF4 (1 mol %) in toluene. The reaction pro-
ceeded to completion within 2 h at ambient temperature to
afford piperidine 3aa in 79% yield (Table 1, entry 1). We
also examined the effect of various counteranions such
as ClO4ꢀ, SbF6ꢀ, OTfꢀ, and Clꢀ, which would act as axial
ligands, on the cationic nature of Co3þ (entries 2ꢀ5).
When [Co(TPP)]SbF6 was used as the catalyst, 3aa was
obtained in 92% isolated yield (entry 3). The desired
Metalloporphyrins have been used as catalysts in var-
ious organic transformations that are difficult to perform
using other metal complexes. The distinct catalytic ability
(1) (a) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558. (b)
Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099. (c)
Weinreb, S. M. Hetero Dienophile Additions to Dienes. In Comprehe-
sive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 5, p 401.
(2) Leighton and coworkers reported novel silicon Lewis acid
mediated aza-DielsꢀAlder reactions of an unactivated imine with three
different dienes, see: Tambar, U. K.; Lee, S. K.; Leighton, J. L. J. Am.
Chem. Soc. 2010, 132, 10248.
(3) For some selected examples on the synthesis and properties of
cationic cobalt-porphyrin complexes, see: (a) Satoh, M.; Ohba, Y.;
Yamauchi, S.; Iwaizumi, M. Inorg. Chem. 1992, 31, 298. (b) Sakurai, T.;
Yamamoto, K.; Naito, H.; Nakamoto, N. Bull. Chem. Soc. Jpn. 1976, 49,
3042. (c) Fukuzumi, S.; Okamoto, K.; Tokuda, Y.; Gros, C. P.; Guilard, R.
J. Am. Chem. Soc. 2004, 126, 17059.
(4) (a) Person, R. G. J. Am. Chem. Soc. 1963, 85, 3533. (b) Ho, T.-L.
Chem. Rev. 1975, 75, 1. (c) Woodward, S. Tetrahedron 2002, 58, 1017.
r
10.1021/ol3020946
XXXX American Chemical Society

product 3aa was not obtained when using other cobalt
catalysts such as [Co(salen)]SbF6 and CoCl2 or when
using AgSbF6 (entries 6ꢀ11). Moreover, noncobalt cati-
onic metalloporphyrin complexes such as [Fe(TPP)]SbF6
and [Mn(TPP)]SbF6 did not show any catalytic activity
(entries 12 and 13).
substituent, which is more easily removable than the
tosyl group, reacted with 2a to yield 3ka in moderate yield
(entry 10).
Table 2. Scope of Imines 1 in the Cycloadditiona
Table 1. Cobalt-Catalyzed Cycloaddition of 1a with 2aa
entry
catalyst
yield (%)b
1
[Co(TPP)]BF4
[Co(TPP)]ClO4
[Co(TPP)]SbF6
[Co(TPP)]OTf
[Co(TPP)]Cl
[Co(salen)] SbF6
CoCl2
79
2
71
3
99 (92)c
69
4
5
<1
6
<1
7
<1
8
CoCl2 (bpy)2
<1
3
9
CoCl2 TPPH2
<1
3
10
11
12
13
CoCl2(tmeda)2
AgSbF6
<1
<1
[Fe(TPP)]SbF6
[Mn(TPP)]SbF6
<1
<1
a Reactions were carried out using catalyst (1 mol %), imine 1a
(0.4 mmol), and 1,3-diene 2a (0.8 mmol, 2 equiv) in 4 mL toluene at
25 °C for 2 h. b NMR yields based on imine 1a. c Isolated yields based
on imine 1a.
With the optimized reaction conditions in hand, we
examined the [Co(TPP)]SbF6-catalyzed [4 þ 2] cycloaddi-
tion of various imines with 2a. The results are summarized
in Table 2. Naphthyl aldimines1b and 1c reacted with 2a in
the presence of the cobalt catalyst to furnish the corre-
spondingly substituted piperidines 3ba and 3ca in 89% and
83% yields, respectively (entries 1 and 2). Imines possess-
ing electron-withdrawing substituents on the phenyl
group, such as 1d and 1e, also reacted with 2a to afford
the correspondingly substituted piperidines 3da and 3ea in
excellent yields (entries 3 and 4). Acetoxy, methoxy, and
nitro substituents were well tolerated under the present
reaction conditions, as seen from the reactions of 1f, 1g, and
1h, and the corresponding cycloaddition products were iso-
lated in good to moderate yields (entries 5, 6, and 7), although
a longer reaction time was required in the latter two cases.
Notably, aliphatic aldimines such as 1i and 1j also reacted
with the simple diene 2a to afford piperidines 3ia and
3ja in 87% and 83% yields, respectively (entries 8 and 9).
Imine 1k bearing a nosyl (Ns: 2-nitrobenzenesulfonyl)
a Reactions were carried out using [Co(TPP)]SbF6 (1 mol %), imine 1
(0.4 mmol), and 1,3-diene 2a (0.8 mmol, 2 equiv) in 4 mL toluene at 25 °C
for 2 h, unless otherwise noted. b Isolated yields based on imine 1.
c [Co(TPP)]SbF6 (2.5 mol %), 25 °C, for 12 h. d [Co(TPP)]SbF6
(2.5 mol %), 50 °C, for 6 h. e NNs, 2-nitrobenzenesulfonamide.
To demonstrate the scope of this cycloaddition in more
detail, we examined the reaction of 1a with various dienes 2
having different functional groups and substitution pat-
terns (Table 3). 2-Phenyl-1,3-butadienes reacted with 1a to
afford the corresponding substituted piperidines 3 regio-
selectively in good yield (entries 1ꢀ4). On the other hand,
B
Org. Lett., Vol. XX, No. XX, XXXX

cis-3ai in 83% yield, with a stereoisomer ratio of 85:15
(entry 8).5,6 Further, the reaction of 1,3-cyclohexadiene
2j with 1a afforded 3aj as the predominant cycloadduct.
Single-crystal X-ray analysis of 3aj confirmed that this
compound was an exo-adduct (see the Supporting
Information).7
Table 3. Scope of Dienes 2 in the Cycloadditiona
Chemoselective activation of imines by the cationic
cobalt catalyst [Co(TPP)]SbF6 was demonstrated by the
[4 þ 2] cycloaddition of 1a with 2a in the presence of
various carbonyl compounds (Scheme 1). The reaction
proceeded effectively to afford the desired piperidine
product 3aa in high yields (>84%), irrespective of the
presence of the carbonyl compound. No cycloadduct
formed by the reaction of 2a with the carbonyl com-
pound was observed in any of these cases. These results
clearly highlighted the excellent chemoselectivity of the
[Co(TPP)]SbF6-catalyzed cycloaddition of imines with
dienes.
Scheme 1. Chemoselective Cycloaddition of 1a with 2a in the
Presence of Various Carbonyl Compounds
In summary, we demonstrated the catalytic efficiency of
the cationic cobalt-porphyrin complex [Co(TPP)]SbF6 for
the aza-DielsꢀAlder reaction of imines with dienes. The
use of this catalyst allowed for the reaction of unactivated
dienes, that is, non-Danishefsky-type dienes, with unacti-
vated imines such as nonglyoxylate imines to construct the
piperidine framework. The high activation ability of the
catalyst that competes with the high chemoselectivity
could be attributed to the hard Lewis acidity of Co3þ
which in turn was due to the rigid tetradentate planar
porphyrin ligand and the weakly coordinating axial SbF6
ligand. Efforts toward the development of an asymmetric
,
ꢀ
a Reactions were carried out using [Co(TPP)]SbF6 (1 mol %), imine
1a (0.4 mmol), and 1,3-diene 2 (0.8 mmol, 2 equiv) in 4 mL toluene
at 25 °C for 2 h, unless otherwise noted. b Isolated yields based on
imine 1. c [Co(TPP)]SbF6 (2.5 mol %), 50 °C, for 2 h. d Ratio of isomers.
e [Co(TPP)]SbF6 (5 mol %), 50 °C, 5 h.
variant of the aza-DielsꢀAlder reaction and elucidation of
(5) The reaction of 1a with (Z)-2-naphthyl-1,3-pentadiene 2i0 in the
presence of the [Co(TPP)]SbF6 catalyst afforded cycloadduct in 81%
yield as a stereoisomer mixture (cis/trans = 57:43), whereas the reaction
of 1a with (E)-2-naphthyl-1,3-pentadiene 2i afforded cis-3ai as the
predominant product (Table 3, entry 8). These results indicated that
the cobalt-catalyzed cycloaddition of imines with dienes proceeds
through a stepwise mechanism.
(6) The cycloadditon of 1b with 2i afforded 3bi as a major isomer in
59% isolated yield. The configuration of 3bi was unambiguously con-
firmed by an X-ray crystal structure analysis (see the Supporting
Information).
(7) The exo-selectivity can be explained by a stepwise reaction
mechanism, which would start with the Alder-ene-type reaction of the
carbonꢀcarbon double bond with the imine to form an allyl cation
intermediate and subsequent cyclization. Thus, geometric isomerization
is induced by the allyl cation formation.
when the butadiene had an electron-donating methoxy
substituent on the phenyl moiety, cycloaddition with 1a
was retarded, and oligomerization of the diene proceeded
predominantly. Cycloaddition of isoprene 2f with 1a af-
forded the desired product 3af in moderate yield (entry 5).
The reaction of conformationally fixed 1,2-bismethylene-
cycloheptane 2g with 1a gave the bicyclic compound 3ag
in 88% yield (entry 6). 2,3-Diphenyl-1,3-butadiene 2h
showed rather low reactivity, and hence, 3ah was obtained
only in moderate yield (entry 7). (E)-2-Naphthyl-1,3-pen-
tadiene 2i reacted with 1a in a regioselective manner to give
Org. Lett., Vol. XX, No. XX, XXXX
C

the unique reactivity of the cationic cobalt-porphyrin
complex are underway.
Dr. Hiroyasu Sato (Rigaku) for the valuable help in X-ray
crystal structural analysis.
Supporting Information Available. Experimental pro-
cedures including spectroscopic and analytical data of
new compounds. CIF files of 3aj and 3bi. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by Grants-
in-Aid from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan. T.K. acknowledges
Tokuyama Science Foundation, and Kurata Memorial
Hitachi Science and Technology Foundation. We thank
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX