Transient azomethine-ylides from a stable amino-carbene and an aldiminium salt

Article abstract of DOI:10.1021/jo026214b

Catalytic amounts of a protic reagent such as tert-butyl alcohol promote the isomerization of a stable amino-aryl-carbene into a transient azomethine ylide. Deprotonation of an alkyl-aldiminium salt also leads to a transient azomethine ylide, but labeling experiments rule out the transient formation of the corresponding amino-alkyl-carbene. The potential hypersurface between model amino-carbene, aziridine, and azomethine ylide is investigated.

Full text of DOI:10.1021/jo026214b

Tr a n sien t Azom eth in e-ylid es fr om a Sta ble Am in o-ca r ben e a n d a n
Ald im in iu m Sa lt
Xavier Cattoe¨n,†,‡ Ste´phane Sole´,† Christian Pradel,† Heinz Gornitzka,† Karinne Miqueu,†
Didier Bourissou,*,† and Guy Bertrand*,†,‡
Laboratoire d’He´te´rochimie Fondamentale et Applique´e du CNRS (UMR 5069), Universite´ Paul Sabatier,
118, route de Narbonne, F-31062 Toulouse Cedex 04, France, and UCR-CNRS J oint Research Chemistry
Laboratory (UMR 2282), Department of Chemistry, University of California,
Riverside, California 92521-0403
gbertran@mail.ucr.edu
Received J uly 19, 2002
Catalytic amounts of a protic reagent such as tert-butyl alcohol promote the isomerization of a
stable amino-aryl-carbene into a transient azomethine ylide. Deprotonation of an alkyl-aldiminium
salt also leads to a transient azomethine ylide, but labeling experiments rule out the transient
formation of the corresponding amino-alkyl-carbene. The potential hypersurface between model
amino-carbene, aziridine, and azomethine ylide is investigated.
In tr od u ction
Herein we report the acid-promoted isomerization of
a stable amino-aryl-carbene8 into a transient azomethine
ylide. In addition, it is shown that the site of deprotona-
tion of N-methyl-aldiminium salts is dependent on the
nature of the substituents. The results are corroborated
by a theoretical study on the interconversion between a
model amino-carbene, aziridine, and azomethine ylide.
Carbenes are typical representatives of neutral reactive
intermediates.1 Their six-valence-electron shell, which
defies the octet rule, is responsible for their fugacity as
well as for their significant synthetic potential. In the
last fifteen years, the isolation of a broad range of singlet
carbenes2,3 and the preparation of persistent triplet
carbenes4 have dramatically advanced this field of chem-
istry. Carbenes are not unique in this respect: 1,3-dipoles
such as nitrilimines5 or azomethine ylides6 are routinely
used transient species that have found numerous ap-
plications in organic synthesis.7
Resu lts a n d Discu ssion
The amino-aryl-carbene 2a , obtained by deprotonation
of the corresponding iminium salt 1a ,8 is stable for
months in the solid state but isomerizes within several
days in tetrahydrofuran solution to afford a novel bicyclic
compound 3a in 35% yield. The structure of 3a , unam-
biguously determined by multinuclear NMR spectroscopy
and by a single-crystal X-ray diffraction study, is some-
what surprising since the aromaticity of the aryl group
is lost. The formation of 3a most likely results from the
electrocyclization of the related azomethine ylide 4a .9
Indeed, 1,3-dipole 4a can be trapped with carbon dioxide,
affording adduct 5a (Scheme 1).
Although several methods are known for the prepara-
tion of azomethine ylides,6 the generation of such a 1,3-
dipole from an amino-carbene, even as a transient
species, has never been reported.10 Therefore, we decided
to investigate the mechanism of the isomerization of 2a
into 4a .
* To whom correspondence should be adressed.
† Universite´ Paul Sabatier.
‡ University of California, Riverside.
(1) (a) Carbene Chemistry; Kirmse, W., Ed.; Academic Press: New
York, 1971. (b) Carbenes; J ones, M., Moss, R. A., Eds.; Wiley: New
York, 1975, Vols. I and II. (c) Carbene (Carbenoide). In Methoden der
Organischen Chemie (Houben-Weyl); Regitz, M., Ed.; Georg Thieme
Verlag: Stuttgart, 1989; Vols. E19b (1-3). (d) Advances in Carbene
Chemistry. Brinker, U. H., Ed.; J ai Press: Greenwich, CT, 1998; Vols.
1 and 2.
(2) (a) Igau, A.; Gru¨tzmacher, H.; Baceiredo, A.; Bertrand, G. J . Am.
Chem. Soc. 1988, 110, 6463. (b) Arduengo, A. J ., III; Harlow, R. L.;
Kline, M. J . Am. Chem. Soc. 1991, 113, 361. (c) Enders, D.; Breuer,
K.; Raabe, G.; Runsink, J .; Teles, J . H.; Melder, J . P.; Ebel, K.; Brode,
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C. P.; Orpen, A. G. J . Am. Chem. Soc. 1998, 120, 11526. (e) Buron, C.;
Gornitzka, H.; Romanenko, V.; Bertrand, G. Science 2000, 288, 834.
(3) For recent reviews on stable singlet carbenes, see: (a) Bourissou,
D.; Guerret, O.; Gabba¨ı, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39.
(b) Herrmann, W. A Angew. Chem., Int. Ed. 2002, 41, 1290. (c)
Arduengo, A. J ., III. Acc. Chem. Res. 1999, 32, 913.
(4) (a) Tomioka, H. Acc. Chem. Res. 1997, 30, 315. (b) Tomioka, H.;
Iwamoto, E.; Itakura, H.; Hirai, K. Nature 2001, 412, 626.
(5) (a) Bertrand, G.; Wentrup, C. Angew. Chem., Int. Ed. Engl. 1994,
33, 527. (b) Shawali, A. S. Chem. Rev. 1993, 93, 2731.
(6) (a) Surpateanu, G.; Lablache-Combier, A. Heterocycles 1984, 22,
2079. (b) Tsuge, O.; Kanemasa, S. In Advances in Heterocyclic
Chemistry; Katritzky, A. L., Ed.; Academic: New York, 1989; Vol. 5,
pp 231-349.
It is conceivable that azomethine ylide 4a might result
from an intramolecular 1,3-migration of a hydrogen atom.
(8) Sole´, S.; Gornitzka, H.; Schoeller, W. W.; Bourissou, D.; Bertrand,
G. Science 2001, 292, 1901.
(9) For the rearrangement of an unsaturated azomethine ylide by
a related electrocyclization process, see: Padwa, A.; Gehrlein, L. J .
Am. Chem. Soc. 1972, 94, 4933.
(7) (a) Caramella, P.; Gru¨nanger, P. In 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, pp 291-
392. (b) Lown, J . W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Vol. 1, pp 653-732.
(10) The only route to azomethine ylides involving carbenes relies
on the reaction of a transient difluorocarbene with a Schiff base:
Novikov, M. S.; Khlebnikov, A. F.; Besedina, O. V.; Kostikov, R. R.
Tetrahedron Lett. 2001, 42, 533.
10.1021/jo026214b CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/20/2002
J . Org. Chem. 2003, 68, 911-914
911

Cattoe¨n et al.
SCHEME 1
SCHEME 2
SCHEME 4
SCHEME 3
contrast to that observed for aryl aldiminium salt 1a , the
amino-alkyl-carbene 2b could not be detected when 1b
was deprotonated with the lithium salt of hexamethyl-
disilazane.13 Instead, the corresponding aziridine 6b14
was obtained in 65% yield and subsequently fully char-
acterized (Scheme 4). The deprotonation of the related
N-CD3 precursor 1c (readily prepared by alkylation of
the imine with deuterated methyl trifluoromethane sul-
fonate) and the C-D iminium salt 1d (obtained in good
yield by successive treatment of tert-butylisocyanide with
tert-butyllithium, deuterated water, and methyl trifluo-
romethane sulfonate) was then studied (Scheme 4).
Aziridines 6c and 6d , featuring two and one deuterium
atom, respectively, were selectively obtained, which rules
out the transient formation of the carbene 2b and
confirms deprotonation at the CX3-N site.
Further information was obtained from theoretical
investigations on the interconversion between amino-
carbene, aziridine, and azomethine ylide. Ab initio cal-
culations were performed at the B3LYP level with the
6-31g(d) basis set on model compounds 2*, 6*, and 3*
(Figure 1, Table 1). Despite the ring strain, aziridine 6*,
the global minimum on the hypersurface, is 20.8 kcal/
mol lower in energy than azomethine ylide 3*. In
contrast, the amino-carbene 2* is only 3.0 kcal/mol above
3*, thanks to the donation of the nitrogen lone pair to
the carbene center. The transition state TS1 between
carbene 2* and aziridine 6* (intramolecular C-H inser-
tion) features a pyramidalized nitrogen atom (ΣN )
This isomerization could be either concerted or stepwise
(C-H insertion/ring-opening sequence) with the transient
formation of the corresponding aziridine 6a (Scheme 2).
However, we observed that protic reagents such as
t-BuOH accelerated the rearrangement of 2a into 3a ,
which suggests an alternative mechanism involving a
protonation/deprotonation sequence, the driving force
being the final electrocyclization of 4a into 3a . This
hypothesis was validated by performing the isomerization
of 2a with 1 equiv of t-BuOD (Scheme 3). Indeed, ca. 50%
of deuterium was incorporated at the carbene carbon
position,11 as expected for a statistic exchange via a
protonation/deprotonation equilibrium. Obviously, tert-
butyl alcohol is not essential and traces of water can play
the same role.
These observations suggest that competitive deproto-
nation reactions of N-methyl aldiminium salts can occur
either at the CH-iminium or at the CH3-N site of the
molecule. Notably, aziridines can be obtained by depro-
tonation of N-methyl ketiminium salts but cannot be
detected from aldiminium salts.12 To favor the deproto-
nation at the CH3-N site, the aldiminium salt 1b,
bearing a σ-electron donating group at the iminium
carbon, was selected as a starting point. In marked
(11) The ratio and position of deuterium incorporation were deter-
mined by 1H NMR and mass spectrometry.
(12) Deyrup, J . A.; Szabo, W. A. J . Org. Chem. 1975, 40, 2048.
(13) A very bulky base is needed to perform this reaction to avoid
addition reactions, as were observed with potassium t-butoxide.
(14) Sheehan, J . C.; Tulis, R. W. J . Org. Chem. 1974, 39, 2264.
912 J . Org. Chem., Vol. 68, No. 3, 2003

Transient Azomethine-ylides
F IGURE 1. Interconversion of amino-carbene 2*, aziridine 6*, and azomethine ylide 3*. Energies (in brackets) are expressed in
kcal/mol relative to the global minimum aziridine 6*. Bond lengths are given in angstro¨ms (Å) and bond angles in degrees (°).
TABLE 1. Bon d Len gth s in An gstr o1m s (Å) a n d Bon d
An gles in Degr ees (°) for th e Differ en t Min im a a n d
Tr a n sition Sta tes
tally. Not surprisingly, starting from azomethine ylide
3*, the activation barrier for ring closure to afford 6(23.0
kcal/mol) is much smaller than that of the 1,3-H migra-
tion (48.7 kcal/mol) leading to the carbene 2*. This is also
in perfect agreement with the intramolecular rearrange-
ment observed for 3b.
2*
6*
3*
TS1
TS2
TS3
C1N
C2N
C3N
C1C2
1.314
1.470
1.477
2.404
1.460
1.460
1.457
1.491
1.338
1.338
1.479
2.415
1.437
1.463
1.472
1.838
1.358
1.366
1.448
2.045
1.296
1.497
1.461
2.237
Con clu sion
C1NC3 127.70 116.19 115.57 112.81 130.98 128.36
C1NC2 119.34 61.42 128.88 78.65 97.30 106.23
C2NC3 112.96 116.11 115.49 112.77 130.27 125.39
Isomerization of a stable amino-aryl-carbene to a
transient azomethine ylide was observed. An intermo-
lecular mechanism involving a protic reagent as a
catalyst is proposed on the basis of labeling experiments
and ab initio calculations. The availability of stable
carbenes allows for the observation of such unusual
rearrangements between highly reactive species. More-
over, suitably substituted aldiminium salts appear to be
convenient precursors for aziridines, which might open
the way for new synthetic developments.
NC1C2 32.20
C1C2N 28.46
59.28
59.29
25.56
25.56
51.32
50.03
41.50
41.20
39.98
33.79
304.2°) and a three-center interaction between the C-H
bond and the carbene center, while the transition state
TS2 between 2* and azomethine ylide 3* (1,3-H migra-
tion) retains a planar nitrogen atom and two unsym-
metrically elongated C-H bonds (1.322 and 1.596 Å). The
large barriers (47.4 and 45.7 kcal/mol, respectively)
predicted for these intramolecular rearrangements
certainly explain why carbene 2a rearranges through
an intermolecular pathway, as determined experimen-
Exp er im en ta l Section
Gen er a l Meth od s. All manipulations were performed
under an inert atmosphere of argon using standard Schlenk
techniques. Dry, oxygen-free solvents were employed.
J . Org. Chem, Vol. 68, No. 3, 2003 913

Cattoe¨n et al.
3a : A tetrahydrofuran solution of carbene 2a was stirred
for a week at room temperature. After evaporation of the
solvent, bicyclic compound 3a was isolated as yellow crystals
in 35% yield by slow evaporation of a saturated diethyl ether
solution. Mp: 104 °C. 19F{1H} NMR (CDCl3): δ -7.3, 11.5. 1H
NMR (CDCl3): δ 1.76 (br, 6H), 1.90 (br, 6H), 2.18 (br, 3H),
tional frequencies. All the investigated structures were char-
acterized by corresponding vibrational analysis to identify
these as energy minima or transition states (one negative
eigenvalue) on the potential energy surface. The connection
between each optimized transition state and the two corre-
sponding minima was confirmed by IRC calculations.
2
2
3.36 (d, J HH ) 11.6 Hz, 1H), 3.92 (d, J HH ) 11.6 Hz, 1H),
X-r a y Cr ysta llogr a p h ic Stu d y. Crystal data for 3a :
C20H21F6N, M ) 389.38, monoclinic, space group P21/n, a )
10.6221(5), b ) 13.3744(6), c ) 12.7429(6) Å, â ) 97.9980(10)°,
V ) 1792.70(14) Å3, Z ) 4, T ) 193(2) K, crystal size 0.3 × 0.4
× 0.6 mm, 2.22° e θ e 26.37°, 3659 reflections (3659
independent, Rint ) 0.0000), 354 parameters, R1 [I > 2σ(I)] )
0.0433, wR2 [all data] ) 0.1033, largest electron density
residue ) 0.267 e/Å3. Data were collected using an oil-coated,
shock-cooled crystal on a Bruker-AXS CCD 1000 diffractometer
with Mo KR (λ ) 0.71073 Å). Semiempirical absorption
coefficients were employed.18 The structure was solved by
direct methods (SHELXS-97)19 and refined using the least-
squares method on F2.20 Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-196175 (3a ). Copies
of the data can be obtained free of charge upon application to
CCDC, 12 Union Road, Cambridge CB2 1 EZ, UK (fax, (+44)
1223-336-033; email, deposit@ccdc.cam.ac.uk).
3
3
5.67 (d, J HH ) 9.3 Hz, 1H), 6.12 (d, J HH ) 5.7 Hz, 1H), 6.40
(dd, J HH ) 9.3 Hz, J HH ) 5.7 Hz, 1H), 7.07 (s, 1H). 13C{1H}
3
3
2
NMR (CDCl3): δ 29.3, 36.1, 41.3, 50.6 (q, J CF ) 27 Hz), 54.6,
54.8, 96.0, 114.3, 117.2, 123.8 (q, 1J CF ) 272 Hz), 125.0 (q, 2J CF
1
) 32 Hz), 126.9 (q, J CF ) 289 Hz), 127.2, 140.6. MS (DCI,
NH3): 389, 320. Anal. Calcd for C20H21F6N: C, 61.69; H, 5.44;
N, 3.60. Found: C, 61.87; H, 5.67; N, 3.48.
5a : Carbon dioxide was bubbled through a tetrahydrofuran
solution of carbene 2a at -78 °C. After 1 week at this tem-
perature, compound 5a was obtained in 44% yield according
to 19F fluorine spectroscopy and characterized without further
purification. 19F{1H} NMR (C4D8O, 193 K): δ 19.4, 20.5. 1H
NMR (C4D8O, 193 K): δ 1.70 (br, 6H), 1.76 (br, 6H), 1.98 (br,
2
2
3H), 3.57 (d, J HH ) 15.6 Hz, 1H), 3.92 (d, J HH ) 15.6 Hz,
3
3
1H), 6.52 (s, 1H), 7.96 (t, J HH ) 8.0 Hz, 1H), 8.22 (d, J HH
)
8.0 Hz, 1H), 8.32 (d, 3J HH ) 8.0 Hz, 1H). 13C{1H} NMR (C4D8O,
193 K): δ 30.3, 36.9, 40.0, 55.1, 85.7, 124.6 (q, 1J CF ) 275 Hz),
130.0, 133.1, 134.1, 139.4, 172.2.
Ack n ow led gm en t. Thanks are due to the CNRS,
the University Paul Sabatier (France), the “Socie´te´ de
Secours des Amis des Sciences”, and the University of
California at Riverside for financial support of this work.
Gen er a l P r oced u r e for 6b-d : A tetrahydrofuran solution
(3 mL) of the iminium salt 1b-d (0.3 mmol) was added
dropwise at -78 °C to a tetrahydrofuran solution (2 mL) of
the lithium salt of hexamethyldisilazane (0.4 mmol). After 30
min, the reaction mixture was allowed to warm to room
temperature. The solvent was evaporated under vacuum and
the crude residue purified chromatographically on neutral
alumina (pentane and diethyl ether) to afford 6b-d as pale
yellow oils in 65% yield.
Su p p or tin g In for m a tion Ava ila ble: Experimental and
theoretical details, spectroscopic data, and X-ray crystal-
lographic data for compound 3a . This material is available free
of charge via the Internet at http://pubs.acs.org.
1
6b. H NMR (C6D6): δ 0.85 (s, 9H), 0.94 (s, 9H), 1.24 (dd,
J O026214B
1H, J HH ) 6.1 and 0.6 Hz), 1.25 (dd, 1H, J HH ) 3.3 and 0.6
Hz), 1.41 (dd, 1H, J HH ) 6.1 and 3.3 Hz). 13C{1H} NMR
(C6D6): δ 22.0, 26.5, 26.9, 30.0, 41.6, 52.0. MS (EI): 155, 140,
98. Anal. Calcd for C10H22N: C, 76.85; H, 14.19; N, 8.96.
Found: C, 77.12; H, 14.48; N, 8.65.
(15) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.7; Gaussian, Inc.: Pittsburgh, PA,
1998.
(16) (a) Becke, A. D. Phys. Rev. 1988, A38, 3098. (b) Becke, A. D. J .
Chem. Phys. 1993, 98, 5648.
(17) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. 1988, B37, 785.
(18) SADABS, Program for Data Correction; Bruker-AXS: Madison,
WI, 2001.
(19) Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467.
(20) Sheldrick, G. M. SHELXL-97, Program for Crystal Structure
Refinement; University of Go¨ttingen, Go¨ttingen, Germany, 1997.
6c. MS (EI), calcd relative abundances for the [(M - CH3)+]
signal of C10H20D2N: 141, 4.0; 142, 100; 143, 10.7. Found: 141,
0.3; 142, 100; 143, 12.
6d . 13C{1H} NMR (C6D6): δ 42.0 (t, 1J CD ) 24 Hz). MS (EI):
calcd relative abundances for the [(M - CH3)+] signal for
C
10H21DN: 140, 4; 141, 100; 142, 12. Found: 140, 22; 141, 100;
142, 10.
Com p u ta tion a l Deta ils. All calculations were carried out
with the Gaussian 98 set of programs.15 The different struc-
tures were optimized at the B3LYP level with the 6-31g(d)
basis set augmented with polarization functions on the heavy
atoms. This functional is built with Becke’s three-parameter
exchange functional16 and the Lee-Yang-Parr correlation
functional.17 All energies were zero-point energies (ZPEs), and
the temperature was corrected using unscaled density func-
914 J . Org. Chem., Vol. 68, No. 3, 2003