Preparation of 13C4-6-methyl anthranilic ester via a Diels-Alder-type process. An experimental and theoretical study to characterize an unexpected isotope exchange

Article abstract of DOI:10.1021/ol051433f

(Chemical Equation Presented) Buta-2,3-dienoate reacts with vinyl ketenimine to give the corresponding substituted aniline through a Diels-Alder cycloaddition. Besides the expected Diels-Alder adduct 3a, the aniline 3b was also obtained in a ratio of 91:9

Full text of DOI:10.1021/ol051433f

ORGANIC
LETTERS
13
2005
Vol. 7, No. 17
3773-3776
Preparation of C4-6-Methyl Anthranilic
Ester via a Diels−Alder-Type Process.
An Experimental and Theoretical Study
to Characterize an Unexpected Isotope
Exchange
|
J. Lorenzo Alonso-Go´mez, Yolanda Pazos,†,§ Armando Navarro-Va´zquez,‡
|
Johan Lugtenburg,† and M. Magdalena Cid*,
Departamento de Qu´ımica Orga´nica, UniVersidade de Vigo, 36310 Vigo, Spain,
Laboratorio de Endocrinolog´ıa Molecular, AÄ rea de InVestigacio´n del Complejo
Hospitalario UniVersitario de Santiago de Compostela, 15706 Santiago de
Compostela, Spain, Departamento de Qu´ımica Orga´nica, UniVersidade de
Santiago de Compostela, 15706 Santiago de Compostela, Spain, and Leiden Institute
of Chemistry, Gorlaeus Laboratory, Leiden UniVersity,
P.O. Box 9502, 2300 RA Leiden, The Netherlands
mcid@uVigo.es
Received June 21, 2005
ABSTRACT
Buta-2,3-dienoate reacts with vinyl ketenimine to give the corresponding substituted aniline through a Diels
−
Alder cycloaddition. Besides the
expected Diels
a reversible [2
−
Alder adduct 3a, the aniline 3b was also obtained in a ratio of 91:9. The observed 13C exchange is explained on the basis of
+
2] cycloaddition competing with the [4
2] concerted one.
+ 2] process. This is supported by B3LYP DFT computations, as a stepwise pathway
lies very close in energy to the [4
+
It has been reported that a vinyl ketenimine and a dienophile
undergo a [4 + 2] cycloaddition reaction in such a way that
the terminal vinylic carbon becomes attached to the electron-
deficient carbon of the dienophile partner, the dienophile
being an alkene1 or an alkyne.2 In fact this is a very
convenient method to synthesize either cyclohexanones or
substituted anilines.3 We successfully have used 2,N-bistri-
isopropylsilyl-1,3-butadiene ketenimine (1) and methyl 2-
butynoate in the synthesis of anthranilic acid.4 For our
biochemical studies it was necessary to introduce 13C-labeling
in the aromatic core, but when we approached the synthesis
of benzyl (1,2,3,4-13C4)-2-butynoate using a reported pro-
cedure,5 the compound we obtained instead was the corre-
sponding allene isomer 2. However, we envisioned that these
allenes could also be used as the dienophile partners in a
Diels-Alder reaction with vinyl ketenimine in order to
obtained substituted anilines.
| Universidade de Vigo.
† Leiden University.
‡ Universidade de Santiago de Compostela.
§ Complejo Hospitalario Universitario de Santiago de Compostela.
(1) Sonveaux, E.; Ghosez, L. J. Am. Chem. Soc. 1973, 95, 5413.
(2) Differding, E.; Vandevelde, O.; Roekens, B.; Trieu Van, T.; Ghosez,
L Tetrahedron Lett. 1987, 20, 397.
(3) Van Liemt, W. B. S.; van Henegouwen, W. G. B.; van Rijn, A.;
Lugtenburg, J. Rec. TraV. Chim. Pays-Bas 1996, 115, 431.
(4) Boers, R. B.; Pazos-Randulfe, Y.; van der Haas, H. N. S.; van
Rossum-Baan, M.; Lugtenburg, J. Eur. J. Org. Chem. 2002, 2094.
(5) Hendrickson, J. B.; Hussoin, S. Synthesis 1989, 217.
10.1021/ol051433f CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/26/2005

Here we report our findings regarding the cycloaddition
reaction between the 2,N-bistriisopropylsilyl-1,3-butadiene
ketenimine (1)6 and benzyl (1,2,3,4-13C4)-2,3-butadienoate
(2)7. Thus, when a mixture of ketenimine 1 and allene 2 was
heated in toluene at 150 °C for 19 h, benzyl 6-methyl-2-(N-
triisopropylsilyl)amino-3-triisopropylsilyl benzoate was ini-
tially afforded, which was desilylated using HCl and
potassium fluoride in methanol under reflux for 2 h, giving
the aniline 3a and 3b in 46% overall yield (Scheme 1).
area of resonance between 2.25 and 2.60 ppm and that of
the area corresponding to the signal at 2.43 ppm, this new
signal being due to the 13C labeling-loss of the methyl group.
(Figure 1).
On the basis of these facts, this intriguing result could be
explained by a curious and unexpected exchange of carbons
between the diene and dienophile moieties during the
cycloaddition as illustrated in Scheme 2.
Thus, we propose the bisallylic biradical 4 as the key
intermediate that would lead to the expected compound 6a,
bissilylated tautomer of 3a, (path i) or instead could rotate
180° around C-5-C-6 bond (path ii) to yield the crucial
cyclobutyl derivative 5 through a [2 + 2] cycloaddition. Next,
compound 5 could provide, via a retro [2 + 2] reaction,
biradical 4a or the isotopomer 4b, depending on which bond
is broken, that would ultimately afford compound 6b,
bissilylated tautomer of compound 3b.
Scheme 1. Preparation of Methyl Anthranilic Ester
To validate this mechanistic proposal we carried out a
computational study on the different possible pathways this
process may follow. To reduce computer costs and complex-
ity of the potential surface we used vinyl ketenimine 1c (R
) H) and allene aldehyde 2c (R′ ) H) as a model system,
whose reaction energetics should not be essentially different
from that of the experimental system.
The 1H NMR spectra of benzyl 6-methylanthranilic ester
(Figure 1) showed not only the expected 13C-labeled product
The mechanism proposed in this work involves several
open-shell singlet biradicals as intermediates. It is known
that DFT, specially hybrid functionals, can efficiently handle
biradical species8 in medium-large-sized systems when
broken-spin symmetry Kohn-Sham determinants (UBS)9 are
used.
All structures in this work have been optimized at the
B3LYP10/6-31+G*11 level of theory, using an unrestricted
approach for open-shell singlet and triplet species. Wave
function stability checks12 have been performed on species
with potential external instabilities. Harmonic frequencies
have been computed analytically to characterize stationary
Figure 1. 400 MHz 1H NMR spectrum of isotopomers 3a and 3b
in CD3Cl.
3a, 2.43 (ddd, J ) 128.0, 5.9, 4.0 Hz, H-6a) and 6.53 (m,
H-5) ppm, but also the isotopomer 3b, 2.43 (dd, J ) 5.5
and 4.1 Hz, H-6a) and 6.53 (dt, J ) 160.7 and 7.1 Hz, H-5).
The 13C NMR showed an intense characteristic signal for
C-5: 120.4 (dd, J ) 58.6 and 4.6 Hz) ppm. These signals
indicated that there was a minor amount of a compound not
labeled in the expected methyl at C-6 position but in the
C-5 aromatic carbon, as denoted by the presence of the
double triplet centered at 6.53 ppm and double doublet at
2.43 ppm and supported by the increased 13C signal at 120.4
1
ppm in the H-decoupled carbon spectrum indicating that
C-5 has been 13C-enriched. The ratio between them was
determined to be 91:9 by measuring the integral of the whole
Figure 2. B3LYP/6-31+G* transition structures in the concerted
and stepwise pathways for 1c + 2c [4 + 2] and [2 + 2]
cycloadditions. Bonds distances are given in Å.
(6) It was prepared as reported in ref 2.
3774
Org. Lett., Vol. 7, No. 17, 2005

Scheme 2. Plausible Mechanism for the Exchange of Position a and b
Scheme 3. Proposed Mechanism for the Cycloaddition Reaction
points and to get ZPVE corrections and free energies. All
However this structure is well described by a restricted
determinant and does not present any RHF f UHF instabil-
ity. Reaction and activation free energies (∆G423.15K) for this
process are -22.8 and 40.6 kcal/mol, respectively, and
formation of singlet biradical 4c can take place with a close
barrier of 41.6 kcal/mol through transition structure 8 (shown
in Figure 2). Hence, the stepwise biradical pathway can
compete efficiently with the concerted reaction. The low
cycloaddition yield (46%) could also be interpreted as
evidence for a stepwise vs a concerted mechanism.14
An alternative pathway beginning with C-1-C-2 formation
is much more disfavored as a result of the vinylic nature of
the formed singlet biradical 11, with a high barrier of 56.4
kcal/mol, corresponding to transition structure 10. Biradical
11 is predicted to be 43.6 kcal/mol higher in energy than
the reactants. (Scheme 3)
computations were performed with the Gaussian03 package.13
The concerted transition structure 7 for cycloaddition of
ketenimine 1c and allene 2c to give the adduct 6c has a very
asynchronous nature, with the C-5-C-6 bond being much
shorter than the C-1-C-2 (2.009 vs 3.240 Å) (Figure 2).
(7) Its synthesis is given in Supporting Information from benzyl
3-oxobutanoate, which was prepared from ethyl oxobutanoate: Mottet, C.;
Hamelin, O.; Garavel, G.; Depre´s, J.-P.; Greene, A. E. J. Org. Chem. 1999,
64, 1380.
(8) Schreiner, P. R.; Navarro-Va´zquez, A.; Prall, M. Acc. Chem. Res.
2005, 38, 29.
(9) (a) Cremer, D.; Filatov, M.; Polo, V.; Kraka, E.; Shaik, S. Int. J.
Mol. Sci. 2002, 3, 604. (b) Polo, V.; Kraka, E.; Cremer, D. Theor. Chem.
Acc. 2002, 107, 291.
(10) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee,
C.; Yang, W.; Parr, R. G. Phys. ReV. B. 1988, 37, 785.
(11) Hehre, W.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986.
(12) Bauernschmitt, R.; Ahlrichs, R. J. Chem. Phys. 1996, 104, 9047.
(13) Gaussian 03, Revision B.05; Frisch, M. J. et al; Gaussian, Inc.,
Wallingford CT, 2004. See Supporting Information for full citation.
(14) (a) Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1993, 115, 7478. (b)
Goldstein, E.; Beno, B.; Houk, K. N. J. Am. Chem. Soc. 1996, 118, 6036.
Org. Lett., Vol. 7, No. 17, 2005
3775

Table 1. Enthalpies and Free Energies (kcal/mol) for All Computed Species
species
7endo
7exo
6c
8
4c
9
10
11
28
43.6
12
13
5c
14
a
∆H0
23.4
40.6
25.7
43.0
-42.8
-22.8
25.2
41.6
9.6
25.5
13.3
32.0
39.6
56.4
32.3
50.5
16.4
34.6
-19.0
-0.9
15.6
33.9
a
∆G423.15K
a Relative to 1c + 2c.
The biradical pathway opens the possibility of a [2 + 2]
cyclization to give the cyclobutyl derivative 5c. Collapse
from singlet biradical 4ca to closed-shell species 5c takes
place with a low barrier (∆G423.15K) of 9.1 kcal/mol. This
species can revert to singlet biradical 4cb through transition
state 14 with an associated barrier of 34.8 kcal/mol, this last
step being responsible for the exchange of the 13C labels
(Scheme 4). This study shows that using stable isotopes in
conjunction with theoretical methods gives structural and
functional information about otherwise completely hidden
processes.
Acknowledgment. We thank CESGA for allocation of
computer time and MCYT, Spain (SAF2001-3288) and The
Chemical Sciences Council of The Netherlands Organization
for Scientific Research (CW-NOW) for financial support.
J.L.A.-G. thanks a F.P.I. fellowship. Y.P. is currently a
recipient of a research contract from Instituto Carlos III,
Ministerio de Sanidad y Consumo. We also thank Prof. Luis
Mun˜oz for stimulating discussions.
Scheme 4. Stepwise [2 + 2] Cycloaddition
Supporting Information Available: Cartesian coordi-
nates for all computed structures; tables with absolute, ZPVE
energies, imaginary frequencies and representation of as-
sociated vectors; experimental procedures; characterization
for compounds 2 and 3 (1H NMR, 13C NMR, HRMS); and
full Gaussian03 citation. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL051433F
3776
Org. Lett., Vol. 7, No. 17, 2005