Proline-catalyzed direct inverse electron demand diels-alder reactions of ketones with 1,2,4,5-tetrazines

Article abstract of DOI:10.1021/ol800417q

An organocatalytic direct inverse electron demand Diels-Alder reaction of ketones with 1,2,4,5-tetrazines has been developed. The process is efficiently catalyzed by proline to give Diels-Alder adducts pyridazines in high yields.

Full text of DOI:10.1021/ol800417q

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1923-1926
Proline-Catalyzed Direct Inverse Electron
Demand Diels–Alder Reactions of
Ketones with 1,2,4,5-Tetrazines
Hexin Xie, Liansuo Zu, Hanine R. Oueis, Hao Li, Jian Wang, and Wei Wang*
Department of Chemistry & Chemical Biology, UniVersity of New Mexico,
Albuquerque, New Mexico 87131-0001
wwang@unm.edu
Received February 22, 2008
ABSTRACT
An organocatalytic direct inverse electron demand Diels–Alder reaction of ketones with 1,2,4,5-tetrazines has been developed. The process is
efficiently catalyzed by proline to give Diels–Alder adducts pyridazines in high yields.
Substituted and/or functionalized pyridazines have received
increasing interest in the fields of inorganic, organic, and
medicinal chemistry.1 3,6-Di(pyridin-2-yl)pyridazines (DPPs)
are well-known ligands for the self-assembly of [2 × 2]
gridlike metal complexes with copper(I) and silver(I) ions,
which afford unique properties.2 The functionalized py-
ridazines are versatile building blocks in natural-product
syntheses3 and have received much attention in physical
organic chemistry.4 Moreover, the pyridazine-based scaffolds
have been explored in medicinal chemistry and as new
R-helix mimetics in peptide and peptidomimetic
chemistry.5Accordingly, the preparation of the molecular
architectures is of considerable synthetic significance. Among
the most widely utilized synthetic methods are the well-
defined inverse electron demand Diels–Alder reactions of
the reactive and readily accessible substituted 1,2,4,5-
tetrazines with electron-rich dienophiles.1 Despite the fact
that electron rich enolates and enamines often used as
dienophiles can facilitate the cycloaddition process and
(1) For reviews of inverse electron demand Diels-Alder reactions for
synthesis of pyridazines, see:(a) Boger, D. L. Chem. ReV. 1986, 86, 781.
(b) Boger, D. L.; Patel, M. Prog. Hetercycl. Chem. 1989, 1, 30. (c) Sauer,
J. ComprehensiVe Heterocyclic Chemistry II; Pergamon: London, 1996;
Vol. 6, p 901.
(2) Examples of pyridazines in applications of inogranic chemistry,(a)
Youinou, M.-T.; Rahmouni, N.; Fischer, J.; Osborn, J. A. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 775. (b) Baxter, P. N. W.; Lehn, J.-M.; Kneisel,
B. O.; Fenske, D. Angew. Chem., Int. Ed. Engl. 1997, 36, 1978. (c)
Weissbuch, I.; Baxter, P. N. W.; Kuzmenko, I.; Cohen, H.; Cohen, S.; Kjaer,
K.; Howes, P. B.; Als-Nielsen, J.; Lehn, J.-M.; Leiserowitz, L.; Lahav, M.
Chem. Eur. J. 2000, 6, 725. (d) Hoogenboom, R.; Kickelbick, G.; Schubert,
U. S. Eur. J. Org. Chem. 2003, 4887. (e) Hoogenboom, R.; Wouters, D.;
Schubert, U. S. Macromolecules 2003, 36, 4743.
(4) For examples of inverse electron demand Diels-Alder reactions
involving pyridazines in applications of physical ogranic chemistry, see:
(a) Carboni, R. A.; Lindsey, R. V. J. Am. Chem. Soc. 1959, 81, 4342. (b)
Wijnen, J. W.; Zavarise, S.; Engberts, J. B. F. N. J. Org. Chem. 1996, 61,
2001. (c) Heldmann, D. K.; Sauer, J. Tetrahedron Lett. 1997, 38, 5791. (d)
Sauer, J.; Heldmann, D. K.; Hetzenegger, J.; Krauthan, J.; Sichert, H.;
Schuster, J. Eur. J. Org. Chem. 1998, 2885. (e) Yu, Z.-X.; Dang, Q.; Wu,
Y.-D. J. Org. Chem. 2001, 66, 6029. (f) Helm, M. D.; Moore, J. E.; Plant,
A.; Harrity, J. P. A. Angew. Chem., Int. Ed. 2005, 44, 3889.
(3) Examples of inverse electron demand Diels-Alder reactions involving
pyridazines in natural product syntheses, see:(a) Boger, D. L.; Coleman,
R. S. J. Am. Chem. Soc. 1987, 109, 2717. (b) Boger, D. L.; Schaum, R. P.;
Garbaccio, R. M. J. Org. Chem. 1998, 63, 6329. (c) Sparey, T. J.; Harrison,
T. Tetrahedron Lett. 1998, 39, 5873. (d) Boger, D. L.; Hong, J.; Hikota,
M.; Ishida, M. J. Am. Chem. Soc. 1999, 121, 2471. (e) Boger, D. L.; Hong,
J. J. Am. Chem. Soc. 2001, 123, 8515. (f) Bodwell, G. J.; Li, J. Angew.
Chem., Int. Ed. 2002, 41, 3261. (g) Bodwell, G. J.; Li, J. Org. Lett. 2002,
4, 127.
(5) Examples of pyridazines in applications of medicinal and peptide
chemistry, see:(a) Dang, Q.; Liu, Y.; Erion, M. D. J. Am. Chem. Soc. 1999,
121, 5833. (b) Sakya, S. M.; Strohmeyer, T. W.; Lang, S. A.; Lin, Y.-I.
Tetrahedron Lett. 1997, 38, 5913. (c) Che, D.; Siegl, J.; Seitz, G.
Tetrahedron: Asymmetry 1999, 10, 573. (d) Che, D.; Wegge, T.; Stubbs,
M. T.; Seitz, G.; Meier, H.; Methfessel, C. J. Med. Chem. 2001, 44, 47. (e)
Volonterio, A.; Moisan, L.; Rebek, J., Jr Org. Lett. 2007, 9, 3733.
10.1021/ol800417q CCC: $40.75
Published on Web 04/15/2008
2008 American Chemical Society

Scheme 1
.
Secondary Amine-Catalyzed Inverse Electron
Demand Diels-Alder Reactions
Table 1. Exploration of Secondary-Amine-Promoted Inverse
Electron Demand Diels-Alder Reaction of Cyclohexanone 1a
with 3,6-Di(pyridine-2-yl)-1,2,4,5-Tetrazine 2aa
entry catalyst solvent conversion (%)b yield (%)b 3a/7c
1
2
3
4
5
6
I
I
I
I
I
I
I
I
II
III
IV
V
CH3CN
H2O
EtOH
CHCl3
neat
DMSO
DMSO
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
100
68
100
93
100
100
100
100
50
<5
100
90
84
32
88
68
8.3:1
1.1:1
7.4:1
2.6:1
7.1:1
>50:1
>50:1
>50:1
1.5:1
NDd
87
provide one-pot access to pyridazines,6 the preformation of
these species are generally required from the corresponding
ketones and aldehydes. From the viewpoint of atom economy,
direct reactions of readily available aldehydes and ketones
are more attractive. Recently, Schubert and co-workers
described a microwave-assisted direct approach to the
synthesis of pyridazines from ketones and aldehydes.7
However, the process suffers from low reaction yields
(typical yields ranging from 9 to 75%), high reaction
temperatures (120–200 °C), and relatively long reaction times
(20–60 min) for a microwave-assisted reaction.
In this Communication, we wish to disclose the results of
our investigation, which has led to a novel organocatalytic
direct inverse electron demand Diels–Alder reaction of
ketones with 1,2,4,5-tetrazines.8 The process is efficiently
catalyzed by simple amino acid L-proline and affords a direct
approach to synthetically and medically useful substituted
pyridazines. Significantly, the products are produced in high
efficiency (75–98% yield) under mild reaction conditions
with a broad substrate scope.
100
100
100
22
trace
4
7e
8f
9
10
11
12
13
NDd
11
0
NDd
none
0
NDd
a Unless specified, a mixture of cyclohexanone 1a (32 µL, 0.3 mmol),
3,6-di(pyridine-2-yl)-1,2,4,5-tetrazine 2a (24 mg, 0.10 mmol), and catalyst
(0.02 mmol) in a specified solvent (0.5 mL) were stirred at 100 °C for 1 h.
b Determined by 1H NMR the crude product with 1,1,2,2-tetrachloroethane
as internal standard. c Determined by 1H NMR. d Not determined. e Reaction
run using 5 mol % catalyst. f Reaction performed at rt for 25 h.
carbonyl compounds in organocatalysis,9 we hypothesized
that in situ formed enamines 4 derived from ketones 1 in
the presence of an amine could serve as nucleophiles for an
inverse electron demand Diels–Alder reaction with 1,2,4,5-
tetrazines 2 (Scheme 1). The Diels–Alder adducts 5 under-
went a subsequent retro-Diels–Alder process to generate
intermediates 6, which proceeded a spontaneous elimination
reaction to give rise to pyridazines 3 and release the catalyst.
The novel catalytic cascade process represents the first
example of employing an organocatalytic one-pot access to
pyridazines 3 from simple starting materials.
Given the success of secondary amines as a general
strategy for catalyzing the formation of enamines from
(6) For selected examples of enamines and enols for inverse electron
demand Diels-Alder reactions with 1,2,4,5-tetrazine, see:(a) Benson, S. C.;
Gross, J. L.; Snyder, J. K. J. Org. Chem. 1990, 55, 3257. (b) Haider, N.
Tetrahedron 1991, 47, 3959. (c) Kotschy, A.; Hajos, G.; Messmer, A. J.
Org. Chem. 1995, 60, 4919. (d) Kotschy, A.; Hajos, G.; Timári, G.;
Messmer, A. J. Org. Chem. 1996, 61, 4423. (e) Panek, J. S.; Zhu, B.
Tetrahedron Lett. 1996, 37, 8151. (f) Kotschy, A.; Smith, D. M.; Bényei,
A. C. Tetrahedron Lett. 1998, 39, 1045. (g) Kotschy, A.; Novák, Z.; Vincze,
Z.; Smith, D. M.; Hajos, G. Tetrahedron Lett. 1999, 40, 6313. (h) Soenen,
D. R.; Zimpleman, J. M.; Borger, D. L. J. Org. Chem. 2003, 68, 3593. (i)
Kotschy, A.; Farago, J.; Csampai, A.; Smith, D. M. Tetrahedron 2004, 60,
3421. (j) Suen, Y. F.; Hope, H.; Nantz, M. H.; Haddadin, M. J.; Kurth,
M. J. J. Org. Chem. 2005, 70, 8468. (k) Hamasaki, A.; Ducray, R.; Boger,
D. L. J. Org. Chem. 2006, 71, 185.
To demonstrate the feasibility of the proposed organo-
catalytic inverse electron demand Diels–Alder reaction, we
carried out a model reaction between cyclohexanone 1a (3.0
equiv) with 3,6-di(pyridine-2-yl)-1,2,4,5-tetrazine 2a (1.0
(9) For reviews of amine catalyzed reactions, see:(a) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Notz, W.; Tanaka, F. Barbas,
C. F., III. Acc. Chem. Res. 2004, 37, 580. (c) Special Issue on Asymmetric
Organocatalysis: Houk, K. N.; List, B. Acc. Chem. Res. 2004, 37, 487. (d)
Berkessel, A.; Groger, H. Asymmetric Organocatalysis-From Biomimetic
Concepts to Applications in Asymmetric Synthesis; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, Germany, 2005. (e) Guillena, G.; Ramón,
D. J. Tetrahedron: Asymmetry 2006, 17, 1465. (f) Mukherjee, S.; Yang,
J. W.; Hoffmann, S; List, B. Chem. ReV 2007, 107, 5471. and cited
references therein.
(7) Hoogenboom, R.; Moore, B. C.; Schubert, U. S. J. Org. Chem. 2006,
71, 4903.
(8) To our knowledge, only two examples of organocatalytic inverse
electron demand Diels-Alder reactions have been described so far:(a) Juhl,
K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498. (b) Samanta,
S.; Krause, J.; Mandal, T.; Zhao, C.-G. Org. Lett. 2007, 9, 2745.
1924
Org. Lett., Vol. 10, No. 10, 2008

equiv) in the presence of 20 mol % secondary amine in
CH3CN at 100 °C (Table 1). Examination of the results of
catalyst screening revealed that the catalyst activities varied
significantly. L-Prolinamide II10 gave 50% conversion with
20% yield for the desired product 3a (entry 9). Unexpectedly,
a significant amount of byproduct 7 was obtained. Surpris-
ingly, diphenylprolinol TMS ether III11 was an ineffective
promoter for the process (entry 10). High conversion for
pyrrolidine IV (entry 11) and morpholine V (entry 12) were
observed; however, the desired product was formed very
Table 2. L-Proline Promoted Inverse Electron Demand
Diels-Alder Reaction of Ketones 1 with 1,2,4,5-Tetrazine 2a
1
poorly. On the basis of H NMR analysis, a complicated
product mixture was observed although starting material 2a
was consumed. In the absence of a secondary amine, as
expected, no reaction occurred (entry 13). Gratifyingly,
L-proline I12 was found to be the best catalyst (Table 1, entry
1). In this instance, a high yield (84%) was achieved. It was
noted that a pronounced amount of byproduct 7 was also
produced. To minimize the formation of the byproduct, we
focused on the optimization of reaction conditions. First, the
effect of solvents on the reaction was probed (entries 1–6).
It was found that DMSO was the optimal reaction medium
for the cascade process; the reaction proceeded efficiently
to give the adduct 3a in a quantitative yield (entry 6). A
control study without catalyst L-proline I showed that only
starting materials remained, indicating that L-proline was the
catalyst for the inverse electron demand Diels–Alder reaction.
Significantly, the formation of the byproduct 7 was not seen
in DMSO. Lowering the catalyst loading from 20 to 5 mol
% did not lead to reducing reaction efficiency (entry 7). The
reaction also proceeded at room temperature to afford desired
product 3a in a quantitative yield without formation of 7
but required long reaction time (25 h) (entry 8).
After establishing the optimal reaction conditions, we
studied the scope of the L-proline-catalyzed inverse electron
demand Diels–Alder reactions. As revealed in Table 2, a
wide range of ketones are suitable for the transformation
(entries 1–9). The reaction was inert to the ring size of
ketones. Five, six, and seven membered cyclic ketones
(entries 1–6) efficiently participated in the process in good
to high yields (83–98%). Furthermore, acyclic ketones were
also good substrates for the process (entries 7–9). It is
noteworthy that the reaction proceeded smoothly when
acetophenone, a challenging substrate in aminocatalysis, was
used as donor (entry 9).13 It appeared that the structural
variation of the diene components 2 had little effect on the
reaction (entries 10–12).
The utilization of unsymmetric ketones could give rise to
the formation of regioisomers. As demonstrated, under the
(10) Review of chiral diarylprolinol ethers catalysis, see:(a) Palomo, C.;
Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876.
(11) L-Prolinamide catalyzed reactions, see:(a) Wang, W; Wang, J.; Li,
H. Org. Lett. 2004, 6, 2817. (b) Wang, J.; Li, H.; Mei, Y.; Lou, B.; Xu, D.;
Xie, D.; Guo, H.; Wang, W. J. Org. Chem. 2005, 70, 5678.
(12) For reviews of proline catalyzed reactions, see:(a) List, B. Tetra-
hedron 2002, 58, 5573.
(13) It has been shown that the use of less reactive aryl alkyl ketones
for chiral secondary-amine-promoted asymmetric aldol reactions generally
gave poor yields and low enantioselectivity. The survey of literature reveals
that only a single study was reported with achieving acceptable yields
(35–93%) but with highly active trichloro- and trifluoroacetaldehydes as
aldol acceptor : Torii, H.; Nakadai, M.; Shihara, K.; Saito, S.; Yamamoto,
H. Angew. Chem., Int. Ed. 2004, 43, 1983.
a Unless specified, see footnote a in Table 1, for all cases 2 equiv of
ketones used. b Isolated yields. c Reaction run using 20 mol % catalyst.
d Reaction run using 10 mol % catalyst.
Org. Lett., Vol. 10, No. 10, 2008
1925

same reaction conditions at 100 °C, two regioisomers 3m
and 3m′ were generated in almost same amount (1). The
reaction temperature had a very limited effect on the
regioselectivity. Decreasing temperature to rt did not result
in a significant alternation of the ratio of product 3m and
3m′.
with a broad substrate scope. The strategy described in this
work affords a direct approach to the preparation of syntheti-
cally and biologically interesting pyridazines from readily
available ketones. Through variation of both dienes and
dienophiles, it is our anticipation that this general organo-
catalytic methodology will stimulate further contributions to
the rapidly growing family of catalytic processes with a
significantly expanded scope.
Acknowledgment. We are grateful for the generous
financial support from the National Science Foundation
(Grant CHE-0704015) and kind gift from the American
Chemical Society-PRF (G1 type).
Supporting Information Available: Experimental pro-
cedures and spectra data for compounds 3a-m′. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, an unprecedented catalytic version of inverse
electron demand Diels–Alder reaction has been successfully
developed. The cascade process is efficiently catalyzed by
simple amino acid L-proline under mild reaction conditions
OL800417Q
1926
Org. Lett., Vol. 10, No. 10, 2008