Synthesis and thermal rearrangement of C,N-dialkynyl imines: A potential aza-Bergman route to 2,5-didehydropyridine

Full text of DOI:10.1021/ja962328r

1464
J. Am. Chem. Soc. 1997, 119, 1464-1465
Scheme 1
Synthesis and Thermal Rearrangement of
C,N-Dialkynyl Imines: A Potential Aza-Bergman
Route to 2,5-Didehydropyridine
Wendi M. David and Sean M. Kerwin*
DiVision of Medicinal Chemistry, College of
Pharmacy, The UniVersity of Texas at Austin
Austin, Texas 78712
ReceiVed July 8, 1996
Although 2,5-didehydropyridine (Scheme 1, B, X ) N) has
been the subject of numerous computational studies,1 there has
not yet been any experimental evidence for the existence of
this elusive intermediate.2 In 1972 Robert Bergman and co-
workers3 reported the thermal rearrangement of dideuterated (Z)-
3-hexene-1,5-diyne (Scheme 1, A, X ) CH) and established
the existence of a 1,4-didehydrobenzene intermediate (B, X )
CH) in this process. We reasoned that a 2,5-didehydropyridine
intermediate might be generated from a C,N-dialkynyl imine
(A, X ) N) in the course of a rearrangement analogous to the
Bergman rearrangement of hex-3-ene-1,5-diyne (A, X ) CH).
We report here a rapid and convenient synthesis of C,N-
dialkynyl imines and the high-yielding conversion of these
compounds to (Z)-â-alkynylacrylonitriles under very mild
thermolysis conditions. Our preliminary studies of this isomer-
ization are in agreement with a proposed mechanism involving
the aza-Bergman rearrangement of the imines to â-alkynylacryl-
onitriles; however, we have not been able to trap the putative
diradical 2,5-didehydropyridine intermediate. Thus, the 2,5-
didehydropyridine species, if generated in this rearrangement,
behaves very differently than 1,4-didehydrobenzene.
Scheme 2
weeks without any signs of decomposition. Both 1a and 1b
display separate resonances in their H and 13C NMR spectra
1
Although C-alkynyl-,4 N-alkynyl-,5 and C,C-dialkynyl imines6
have previously been prepared, C,N-dialkynylimines have not
been reported. Our synthesis of the requisite C,N-dialky-
nylimines 1a,b (Scheme 2) involves alkynylcuprate substitution5
of the oximinosulfonate esters 6 and 7, which are prepared from
the oxime 5. Treating the silyl nitronate 47 with 2 equiv of
lithium phenylacetylide8 affords the previously reported9,10
oxime 5 in modest yield along with variable amounts of
3-methyl-5-phenylisoxazole, which presumably arises from 1,3-
dipolar cycloaddition of an intermediate nitrile oxide with
phenylacetylene. Addition of the cuprate derived from phenyl-
acetylene to the oxime tosylate 6 affords the C,N-dialkynyl imine
1a in 20% yield. The corresponding oxime mesylate 7
undergoes reaction to afford 1a in 38% yield. The imine 1b is
produced in 20% yield upon addition of the cuprate derived
from 6-phenylhex-5-en-1-yne11 to oxime mesylate 7. Imines
1a and 1b are isolated as relatively stable yellow oils after
chromatography. These compounds can be handled in the air
for short periods of time, or stored at -10 °C under argon for
corresponding to (E)- and (Z)-isomers about the imine double
bond (∼1:2 ratio). In the case of imine 1a, these separate
resonances do not coalesce at temperatures up to 60 °C in
benzene or THF (500 MHz); however, we have been unable to
resolve the CdN double bond isomers by TLC or HPLC.
When a benzene solution of 1a is heated under reflux
overnight, nitrile 3a is produced in 88% yield after chroma-
tography (Scheme 3). Nitrile 3a is produced as the (Z)-
stereoisomer (>95%), as judged from the 1H NMR of the crude
thermolysis product and comparison to authentic (E)-3a.12
Heating a solution of imine 1a in benzene containing a large
excess of 1,4-cyclohexadiene (1,4-chd) as a hydrogen atom trap,
or in neat 1,4-chd at 150 °C for 2 h, affords the nitrile 3a as the
only isolable product. The imine 1b contains a pendent double
bond that could serve as an intramolecular trap for the putative
diradical intermediate 2 (Scheme 3). Such a cyclization should
proceed at a rapid rate (ca. 106 s-1);13 indeed, a similar
technique has been used to trap 1,4-didehydrobenzene inter-
mediates formed from Bergman cyclizations.14 We find that
heating a benzene solution of 1b containing a large excess of
1,4-chd affords only the nitrile 3b in nearly quantitative yield.
Nitrile 3b is produced as a single isomer with (Z)-stereochem-
istry about the tetrasubstituted double bond. In none of these
reactions were any products (e.g., 8 or 10) which would arise
from trapping of the putative 2,5-didehydropyridine intermediate
2 detected.
(1) Nam, H. H.; Leroi, G. E.; Harrison, J. F. J. Phys. Chem. 1991, 95,
6514-6519, and references cited therein.
(2) Reinecke, M. Tetrahedron 1982, 38, 427-498, and references cited
therein.
(3) Jones, R. P.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660.
(4) Austin, W. B.; Bilow, N.; Kelleghan, W. J.; Lau,. K. S. Y. J. Org.
Chem. 1981, 46, 2280-2286. Bourgain, M.; Normant, J.-F. Bull. Soc. Chim.
Fr. 1983, 2137-2142.
(5) Wu¨rthwein, E.-U.; Weigmann, R. Angew. Chem. 1987, 99, 918-
919.
Heating solutions of 1a in either acetonitrile or heptane at
110 °C and monitoring the rate of the disappearance of 1a and
(6) Ito, Y.; Inouye, M.; Murakami, M. Chem. Lett. 1989, 1261-1264.
(7) Colvin, E. W.; Beck, A. K.; Bastani, B.; Seebach, D.; Kai, Y.; Dunitz,
J. D. HelV. Chim. Acta 1980, 63, 697-710.
(8) For the addition of alkyl and aryl lithium reagents to silyl nitronates
see: Colvin, E. W.; Robertson, A. D.; Seebach, D.; Beck, A. K. J. Chem.
Soc, Chem. Commun. 1981, 952-953.
(12) Authentic (E)-3a was synthesized by the palladium-catalyzed
coupling of 1-propynyltributyltin and the (E)-enol triflate of 2-cyano-2-
phenylacetophenone.
(13) This value is estimated from that reported for the corresponding
cyclization involving a secondary sp3 radical center: Griller, D.; Ingold,
K. U. Acc. Chem. Res. 1980, 13, 317-323.
(14) Wisniewski Grissom, J.; Calkins, T. L. Tetrahedron Lett. 1992, 33,
2315-2318.
(9) Hamlet, Z.; Ramperdsad, M.; Shearing, D. J. Tetrahedron Lett. 1970,
2101-2104.
(10) Morrocchi, S.; Ricca, A.; Zanarotti, A.; Bianchi, G.; Gandolfi, R.;
Gru¨nanger, P. Tetrahedron Lett. 1969, 3329-3332.
(11) Keinan, E.; Peretz, M. J. Org. Chem. 1983, 48, 5302-5309.
S0002-7863(96)02328-1 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 6, 1997 1465
Scheme 3
dialkynylimines. First, the rearrangement of 1 occurs much
more readily than the Bergman reaction of simple hexene-
diynes.17 Electron withdrawing substituents on the phenyl rings
of 11 have been shown to accelerate its Bergman rearrange-
ment,15 perhaps by decreasing the degree of repulsion of the
in-plane π-orbitals in the transition state.18 The substitution of
an sp2 carbon in 11 with a nitrogen, as in 1, may facilitate the
rearrangement by a similar effect. The overall conversion of 1
to 3 is highly exothermic.19 To the extent that ground state
stabilization of the product of the reaction is reflected in the
transition state, this may also play a role in enhancing the rate
over that of the Bergman reaction. A more important difference
between the Bergman reaction and the rearrangement of C,N-
dialkynylimines involves the evidence for a diradical intermedi-
ate in the former. In contrast, we have been unable to obtain
any evidence for a diradical intermediate in the rearrangement
of 1 to 3.20 This inability to trap diradical species 2 may be
related to the theoretical predictions of a very low energy barrier
for the ring opening reaction of B (Scheme 1, X ) N) to nitrile
C (X ) N).1 Alternatively, the intermediate 2,5-didehydropyri-
dine may not exist as a diradical species but may be more closely
represented by alternative structures, such as D or E (Scheme
1).
In conclusion, C,N-dialkynyl imines undergo a facile thermal
rearrangement to â-alkynylacrylonitriles that is structurally
related to the Bergman rearrangement of (Z)-hexenediynes.
Despite similarities between the Bergman reaction of hexene-
diynes and the rearrangement of C,N-dialkynylimines to (Z)-
â-alkynylacrylonitriles, which lead us to speculate that these
two processes are related mechanistically, there is a clear
dichotomy between the Bergman rearrangement and the rear-
rangement of C,N-dialkynylimines concerning the nature of the
intermediates that are involved.
Table 1. Kinetic Parameters for the Thermal Isomerization of 1a
and 11a
starting material (solvent)
k, s-1 b
t1/2 (τ)b
product
3a
1a
(CH3CN)
1a
2.43 × 10-4 47 min
2.70 × 10-4 43 min
3.24 × 10-7e 24.4 dayse o-terphenyl
3a
(heptane)
11c
(CH3CN + 1,4-chdd)
a See Supporting Information for experimental details. b Average
value for two runs. c (Z)-1,6-Diphenylhex-3-ene-1,5-diyne. d 1,4-Cy-
clohexadiene. e Estimate from a single run of 12 days duration.
the production of 3a gave the first-order rate constants shown
in Table 1. The t1/2 for the thermal isomerization of 1a to 3a
is between 40 and 50 min at 110 °C, regardless of solvent
polarity. The t1/2 for the Bergman cyclization of the corre-
sponding (Z)-1,6-diphenylhex-3-ene-1,5-diyne (11) to o-terphen-
yl is reported to be 71 min at 280 °C.15 We find that prolonged
heating of 11 in acetonitrile containing excess 1,4-chd affords
a first order rate of conversion to o-terphenyl that is about 1000-
fold slower than the rearrangement of 1a to 3a.
Acknowledgment. We are grateful to the donors of the Petroleum
Research Fund, administered by the American Chemical Society, and
to the Robert A. Welch foundation for partial support of this work.
Supporting Information Available: Experimental details, spectral
data for all new compounds reported in the text, and plots of the kinetic
data (12 pages). See any current masthead page for ordering and
Internet access instructions.
JA962328R
As highlighted in Scheme 1, there are structural similarities
between the Bergman rearrangement of hexenediynes and the
rearrangement of C,N-dialkynyl imines to â-alkynylacryloni-
triles. In addition, there are other similarities between these
two reactions. Both reactions occur at rates that are first-order
with respect to starting material and are relatively unaffected
by the polarity of the solvents employed.3 Thus, it appears that
both processes proceed though nonpolar, unimolecular reaction
mechanisms. In addition, both reactions appear to be stereospe-
cific, in that the Bergman reaction requires (Z)-enediynes, and
the rearrangement of 1 produces (Z)-â-acetylenic acrylonitriles
specifically.16
(16) For imine 1, only the isomer with (Z)-stereochemistry about the
imine double bond would be expected to undergo an aza-Bergman reaction.
As the isomeric mixture of imine 1a (∼2:1 Z/E) undergoes first-order
isomerization to nitrile 3a, there is presumably a rapid equilibration between
(E)- and (Z)-imines under the thermolysis reaction conditions. The nature
of this E to Z isomerization remains to be elucidated.
(17) Enediynes which undergo a release of strain upon Bergman
cyclization react at a much faster rate than simple acyclic enediynes such
as 11. See, for example: Magnus, P.; Fortt, S.; Pitterna, T.; Snyder, J. P.
J. Am. Chem. Soc. 1990, 112, 4986-4987.
(18) Koga, N.; Morokuma, K. J. Am. Chem. Soc. 1991, 113, 1907-
1911.
(19) Semi-empirical calculations using the AM1 Hamiltonian have been
used to predict the relative heats of formation for the nitrile C (Scheme 1,
X ) N) and the imine A (X ) N). These calculations predict that nitrile C
lies 34 kcal/mol lower in energy than the imine A.
Despite the similarities noted above, there are key differences
between the Bergman reaction and the rearrangement of C,N-
(20) Nicolaou and co-workers have reported a potential Bergman
rearrangement in which the intermediate 1,4-didehydrobenzene does not
undergo intermolecular trapping: Nicolaou, K. C.; Smith, A. L. Acc. Chem.
Res. 1992, 25, 497-503.
(15) Schmittel, M.; Kiau, S. Chem. Lett. 1995, 953-954.