Lewis acid catalyzed inverse electron-demand diels-alder reaction of 1,2-diazines

Article abstract of DOI:10.1021/ol101701z

A systematic approach toward Lewis acid catalyzed inverse electron-demand Diels-Alder (IEDDA) reactions of 1,2-diazines is described. The general concept is first investigated by DFT calculations, supported by spectroscopic data, and finally proven in the experiment.

Full text of DOI:10.1021/ol101701z

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4062-4065
Lewis Acid Catalyzed Inverse
Electron-Demand Diels-Alder Reaction
of 1,2-Diazines
Simon N. Kessler and Hermann A. Wegner*
Department of Chemistry, UniVersity of Basel, St. Johanns-Ring 19,
Basel 4056, Switzerland
hermann.wegner@unibas.ch
Received July 21, 2010
ABSTRACT
A systematic approach toward Lewis acid catalyzed inverse electron-demand Diels-Alder (IEDDA) reactions of 1,2-diazines is described. The
general concept is first investigated by DFT calculations, supported by spectroscopic data, and finally proven in the experiment.
The Diels-Alder reaction with normal electron-demand has
been established as one of the most utilized reaction types
and offers the great advantage of installing four stereocenters
at once.1 In the shadow of this versatile reaction, the inverse
electron-demand Diels-Alder (IEDDA) reaction has gradu-
ally gained in interest over the past 50 years. Nowadays it
offers a broad application spectrum.2 Following the first
studies of the IEDDA reaction of 3,6-disubstituted 1,2,4,5-
tetrazines,3 a variety of substituted tetrazines and triazines
have been investigated.4 Despite this work, the reaction of
1,2-diazines with electron-rich dienophiles has received less
attention. Reports in the literature are mainly on 1,2-diazines
substituted by electron-withdrawing groups due to the
energetically high lying LUMO of unsubstituted diazines.4
This renders them hardly reactive even toward electron-rich
dienophiles. Therefore, only one dienophile is known to react
with unsubstituted pyridazine,5 a few more to react with
phthalazine 1.6
Herein we describe for the first time an IEDDA reaction
of an unsubstituted phthalazine catalyzed by a bidentate
Lewis acid, 5,10-dimethyl-5,10-dihydroboranthrene (7).7 The
(1) (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogian-
nakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668. (b) Kobayashi, S.;
Jørgensen, K. A. Cycloaddition Reactions in Organic Synthesis; Wiley-
VCH: Weinheim, Germany, 2002. (c) Takao, K.; Munakata, R.; Tadano,
K. Chem. ReV. 2005, 105, 4779.
(4) (a) Boger, D. L. Tetrahedron 1983, 39, 2869. (b) Boger, D. L. Chem.
ReV. 1986, 86, 781. For recent examples of IEDDA reactions with triazines,
see: (c) Xu, G.; Zheng, L.; Wang, S.; Dang, Q.; Bai, X. Synlett 2009, 3206.
(d) Catozzi, N.; Edwards, M. G.; Raw, S. A.; Wasnaire, P.; Taylor, R. J. K.
J. Org. Chem. 2009, 74, 8343. For recent examples of IEDDA reactions
with tetrazines, see: (e) Rahanyan, N.; Linden, A.; Baldridge, K. K.; Siegel,
J. S. Org. Biomol. Chem. 2009, 7, 2082.
(2) For an example for an IEDDA in a total synthesis, see: Bodwell,
G. J.; Li, J. Angew. Chem., Int. Ed. 2002, 41, 3261.
(3) Carboni, R. A.; Lindsey, R. V. J. Am. Chem. Soc. 1959, 81, 4342.
10.1021/ol101701z  2010 American Chemical Society
Published on Web 08/18/2010

idea of the catalysis of the IEDDA reaction of 1,2-diazines
is based on the following rationale: a bidentate Lewis acid
may complex the vicinal nitrogen atoms and thus withdraw
electron density from the diazine. The simultaneous coor-
dination should lower the LUMO of the diene and facilitate
the cycloaddition step according to the FMO theory.8
A variety of bidentate boron-based Lewis acids have been
reported in the literature.9 Although complexation of boron-
based9b-d and indium-based10 bidentate Lewis acid with 1,2-
diazines has been described, to the best of our knowledge,
no example has been reported to exploit this phenomenon
for catalysis in organic synthesis.
The complexes of 1,2-diazines with different bidentate
boron Lewis acids have been geometrically optimized with
DFT at the B3LYP11 level, and the orbital energies have
been calculated with HF theory, both with the 6-31G* split-
valence set,12 using Gaussian 03.13,14
The dihydroboranthrene system 7 was predicted to display
the above desired properties combined with relatively easy
synthetic accessibility. The calculations of the adduct 2 of
phthalazine 1 with dimethyl dihydroboranthrene 7 predict a
significant shift of the LUMO to lower energies (Figure 1).
This result fully supports the initial idea for catalysis of the
IEDDA reaction of diazines.
Figure 1. Relative energies of the FMOs of the uncomplexed
phthalazine 1 in comparison with the 5,10-dimethyl-5,10-dihy-
droboranthrene phthalazine complex 2. The graphics represent the
LUMOs.
The dihydroborantherene 7 was prepared in four steps by
known literature procedures (Scheme 1). The synthesis
commences with a Li/Br exchange and consecutive silylation
to result in 1,2-bis(trimethylsilyl)benzene (4).15 One of the
TMS groups was selectively substituted with BCl3 to give
the monoborinated product 5 according to a procedure
published by Kaufmann.16 The product was dimerized17 at
135 °C, followed by methylation7 with methyl lithium.
With the desired Lewis acid in hand, complexation studies
with 1,2-diazines were conducted to validate the electron-
withdrawing effect predicted by the calculations. Titration
of phthalazine to a solution of 7 resulted in the formation of
a 1:1 complex of the 1,2-diazine with the Lewis acid, as
revealed by 1H NMR spectroscopy: the electron withdrawal
from the 1,2-diazine is reflected by a low field shift of the
diazine protons and, accordingly, a high field shift of the
protons of the Lewis acid (Figure 2). If an electron-rich
dienophile such as the oxazolidine 8 is treated with the Lewis
acid 7, complexation on the N atom is observed. However,
upon addition of phthalazine, the complexation of 7 is
completely shifted to the 1,2-diazene.
(5) (a) Gruseck, U.; Heuschmann, M. Tetrahedron Lett. 1987, 28, 6027.
For intramolecular examples, see: (b) Boger, D. L.; Coleman, R. S. J. Org.
Chem. 1984, 49, 2240. (c) Boger, D. L.; Sakya, S. M. J. Org. Chem. 1988,
53, 1415. In total syntheses: (d) Boger, D. L.; Coleman, R. S. J. Am. Chem.
Soc. 1987, 109, 2717. (e) Boger, D. L.; Zhang, M. J. Am. Chem. Soc. 1991,
113, 4230.
(6) Oishi, E.; Taido, N.; Iwamoto, K.; Miyashita, A.; Higashino, T.
Chem. Pharm. Bull. 1990, 38, 3268.
(7) Schulz, H.; Pritzkow, H.; Siebert, W. Chem. Ber. 1991, 124, 2203.
(8) (a) Fleming, I. Molecular Orbitals and Organic Chemical Reactions;
Wiley: Chichester, UK, 2010. (b) Sauer, J.; Sustmann, R. Angew. Chem.,
Int. Ed. Engl. 1980, 19, 779.
(9) (a) Schulz, H.; Seyffer, H.; Deobald, B.; Pritzkow, H.; Siebert, W.
Z. Naturforsch., B: Chem. Sci. 1994, 49, 465. (b) Piers, W. E.; Irvine, G. J.;
Williams, W. C. Eur. J. Inorg. Chem. 2000, 2131. (c) Ashe, A. J.; Kampf,
J. W.; Schiesher, M. W. Organometallics 2003, 22, 203. (d) Jaska, C. A.;
Emslie, D. J. H.; Bosdet, M. J. D.; Piers, W. E.; Sorensen, T. S.; Parvez,
M. J. Am. Chem. Soc. 2006, 128, 10885.
(10) Gabbai, F. P.; Schier, A.; Riede, J.; Hynes, M. J. Chem. Commun.
1998, 897.
(11) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (b)
Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157,
200. (c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
Scheme 1. Preparation of the Bidentate Lewis Acid 7
(12) (a) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem.
Phys. 1980, 72, 650. (b) McLean, A. D.; Chandler, J. S. J. Chem. Phys.
1980, 72, 5639. (c) Curtiss, L. A.; McGrath, M. P.; Blaudeau, J.-P.; Davis,
N. E.; Binning, R. C., Jr.; Radom, L. J. Chem. Phys. 1995, 103, 6104. (d)
Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer, P. v. R. J. Comput.
Chem. 1983, 4, 294.
(13) Frisch, M. J.; Gaussian 03, revision D.02; see Supporting Informa-
tion.
(14) Bachrach, S. M. Computational Organic Chemistry; Wiley-Inter-
science: Hoboken, NJ, 2007
.
(15) Bettinger, H. F.; Filthaus, M. J. Org. Chem. 2007, 72, 9750.
Alternatively, we developed in our laboratory a new Fe-catalyzed method
to access 1,2-bis(trimethylsilyl)benzenes: Bader, S.; Kessler, S. N.; Wegner,
H. A. Synthesis 2010, 2759.
Org. Lett., Vol. 12, No. 18, 2010
4063

The electron shift in the phthalazine complex 2 in
comparison to their free counterparts was highlighted by
means of DFT and by NMR spectroscopy. All observations
support a decrease of the LUMO energy of the complexed
1,2-diazine. Hence, the cycloaddition step should be facili-
tated.
same reaction time, when nearly no conversion is observed
without the catalyst, the addition of only 5 mol % of complex
2 results in full conversion according to H NMR (isolated
yield 42%). This proves an acceleration of the intended
IEDDA reaction in the presence of the catalyst 7.
1
Figure 2.
Stacking of the low field region of the 1H NMR spectrum
of the complex 2 in green (Nr. 2), the free phthalazine 1 in red
(Nr. 1), and the free Lewis acid 7 in blue (Nr. 3). The singlet THF-
d8 (δ ) 3.58 ppm) is used as the reference peak.
The bidentate Lewis acid 7 was tested as a catalyst in a
model reaction of phthalazine 1 with oxazolidine 8.18 Hu¨nig’s
base was added to capture any protons which might catalyze
the acid promoted polymerization of the oxazolidine 8.18b,c
The reaction was first tested with 10 mol % of the Lewis
acid complex 2. In parallel, the same reaction mixture was
carried out with 5 and 2.5 mol % of the catalyst 2 using 1.5
equiv of the oxazolidine 8 (Figure 3).
Figure 4. Proposed catalytic cycle of the IEDDA reaction of
oxazolidine 8 with phthalazine 1 catalyzed by the bidentate Lewis
acid 7.
The proposed catalytic cycle is displayed in Figure 4.19
The bidentate Lewis acid 7 forms a 1:1 complex 2 with the
phthalazine 1. This complex 2 undergoes the cycloaddition
step with the dienophile resulting in the cycloadduct 9 which
releases dinitrogen to the intermediate 10. In this process
also, the Lewis acid is liberated which now can re-enter the
catalytic cycle by complexing the next 1,2-diazine molecule.
Rearomatization of 10 yields the final product, the substituted
naphthalene 11.
The reaction of phthalazine 1 with oxazolidine 8 in the
presence of a monodentate Lewis acid such as BF3•Et2O
followed a totally different reaction path. None of the IEDDA
1
product 11 was detected in H NMR nor GC-MS analysis.
All results suggest products resulting from a nucleophilic
addition of the oxazolidine. This is similar to a nucleophilic
addition of alkyl lithium reagents mediated by BF3•Et2O.20
1
Figure 3
.
Stacked aromatic region of H NMR (in CDCl3) of the
pure product 11 in red (Nr. 1), the catalyzed reaction with 5.0 and
2.5 mol % of catalyst 7 in green (Nr. 2) and in cyan (Nr. 3), and
the uncatalyzed reaction in purple (Nr. 4).
Besides the oxazolidine 8, a number of other electron-
rich reaction partners can be used to access 2,3-substituted
naphthalenes which are difficult to obtain by other means
(Table. 1).21 Enamines give in good to very good yield the
desired products (Table 1, entries 2-4).22 It is noteworthy
that the enamines can be prepared in situ without disturbing
the activity of the catalyst with the free amine or the water
Comparison of the catalyzed reaction and the noncatalyzed
reaction clearly demonstrates the ability of the bidentate
Lewis acid to promote the IEDDA of phthalazine. After the
(16) Kaufmann, D. Chem. Ber. Rec. 1987, 120, 901.
(19) (a) Hartmann, K.-P.; Heuschmann, M. Angew. Chem., Int. Ed. Engl.
1989, 28, 1267. (b) Hartmann, K.-P.; Heuschmann, M. Tetrahedron 2000,
56, 4213. (c) Ernd, M.; Heuschmann, M.; Zipse, H. HelV. Chim. Acta 2005,
88, 1491.
(17) Schacht, W.; Kaufmann, D. J. Organomet. Chem. 1987, 331, 139.
(18) (a) Schulze, T.; Letsch, J.; Klemm, E. J. Polym. Sci., Part A: Polym
Chem. 1996, 34, 81. (b) Zhou, A.; Pittman, C. U., Jr. Synthesis 2006, 37.
(c) Zhou, A.; Pittman, C. U. J. Comb. Chem. 2006, 8, 262.
(20) Uno, H.; Okada, S.; Suzuki, H. Tetrahedron 1991, 47, 6231.
4064
Org. Lett., Vol. 12, No. 18, 2010

less activated dienophiles, like dihydrofurans, give in moder-
ate to good yield the substituted naphthalenes.24 Alkynes
were, so far, not reactive in the catalyzed IEDDA reaction.
In general, the reactivity of the dienophiles corresponds to
the trend of the kinetic data for 1,2,4,5-tetrazines.25
Table 1. IEDDA-Reaction of phthalazine catalyzed by the
bidentate Lewis acid 7 with different dienophiles.a
In summary, the presented study gives first proof of
principle of catalysis for an IEDDA reaction of nonactivated
1,2-diazines. Investigations to elucidate the mechanism and
the applications of this new methodology are currently
underway.
Acknowledgment. The authors thank Prof. M. Meuwly
(University of Basel, Switzerland) for stimulating discussions,
and the Swiss National Science Foundation for financial
support. The award of a Novartis fellowship in Organic
Chemistry for S.N.K. is gratefully acknowledged, and
H.A.W. is indebted to the Fonds der Chemischen Industrie
for a Liebig-Fellowship.
Supporting Information Available: Experimental details
and characterization data are available. This material is
available free of charge via the Internet at http://pubs.
acs.org.
OL101701Z
(21) General Procedure: To a fine suspension of complex 2 (5.0 mg,
15.0 µmol, 5.00 mol %) and phthalazine 1 (39.0 mg, 0.300 mmol, 1.00
equiv) in diglyme (500 µl) and N,N-diisopropylethylamine (125 µl) was
added 2-ethylidene-3-methyloxazolidine (8) (50.9 mg, 0.450 mmol, 1.50
equiv). The reaction mixture was heated to 120 °C for 20 h. After
evaporation at 50 °C/2 mbar, it was purified by flash chromatography (silica
gel; hexane/ee 19:1 f 4:1, stabilized with 1% Et3N) to yield a colorless oil
(28.4 mg, 42%).
(22) The elimination of the pyrrolidine was completed using m-CPBA:
Chenard, B. L.; Ronau, R. T.; Schulte, G. K. J. Org. Chem. 1988, 53, 5175.
(23) (a) Carlson, R.; Nilsson, A.; Stroemqvist, M. Acta Chem. Scand.,
Ser. B 1983, 37, 7. (b) Snyder, D. C. J. Organomet. Chem. 1986, 301, 137.
(c) For an example of an IEDDA with 1,2,4-triazenes with enamines,
generated in situ, see: Boger, D. L.; Panek, J. S.; Meier, M. M. J. Org.
Chem. 1982, 47, 895.
a With 5 mol % of 2, 1.5-3 equiv of dienophile, 2 equiv of DIEA, and
diglyme. b Enamine was prepared in situ from the corresponding ketone
and pyrrolidine.
(24) (a) The mixture of regioisomers in Table 1, entry 8, is caused by
isomerization of the double bond to the exo-position: (a) Armitage, D. M.;
Wilson, C. L. J. Am. Chem. Soc. 1959, 81, 2437. (b) The elimination to the
aromatic product was completed using UV irradiation: (b) Sauer, J.;
Ba¨uerlein, P.; Ebenbeck, W.; Fu¨llhuber, H.; Gousetis, C.; Wernthaler, K.
Eur. J. Org. Chem. 2001, 3999.
formed. Using this protocol, even linear ketones can be
transformed, where the enamine is difficult to isolate.23 Also
(25) Sauer, J.; Heldmann, D. K.; Hetzenegger, J.; Krauthan, J.; Sichert,
H.; Schuster, J. Eur. J. Org. Chem. 1998, 2885.
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