α,5-didehydro-3-picoline diradicals from skipped azaenediynes: Computational and trapping studies of an aza-Myers-Saito cyclization

Article abstract of DOI:10.1021/ol049266r

Equation presented. On the basis of density functional calculations, the isomerization of skipped azaenediynes (C-alkynyl-N-propargylimines) to azaenyne allenes and subsequent rapid aza-Myers-Saito cyclization to α,5-didehydro- 3-picoline were predicted. We prepared the N-propargylimine of 1-phenyl-3-tri(isopropyl)silylprop-2-yn-1-one, which undergoes proto-desilylation and isomerization to an azaenyne allene when treated with tetrabutylammonium fluoride. In the presence of 1,4-cyclohexadiene, this azaenyne allene affords 6-phenyl-3-picoline and other products corresponding to the trapping of an α,5-didehydro-3-picoline diradical.

Full text of DOI:10.1021/ol049266r

ORGANIC
LETTERS
2004
Vol. 6, No. 12
2059-2062
r,5-Didehydro-3-picoline Diradicals from
Skipped Azaenediynes: Computational
and Trapping Studies of an
Aza-Myers−Saito Cyclization
Liping Feng, Dalip Kumar, David M. Birney, and Sean M. Kerwin*
DiVision of Medicinal Chemistry, College of Pharmacy, The UniVersity of Texas at
Austin, Austin, Texas 78712, and Department of Chemistry, Texas Tech UniVersity,
Lubbock, Texas 79409
skerwin@mail.utexas.edu
Received April 21, 2004
ABSTRACT
On the basis of density functional calculations, the isomerization of skipped azaenediynes (C-alkynyl-N-propargylimines) to azaenyne allenes
and subsequent rapid aza-Myers−Saito cyclization to r,5-didehydro-3-picoline were predicted. We prepared the N-propargylimine of 1-phenyl-
3-tri(isopropyl)silylprop-2-yn-1-one, which undergoes proto-desilylation and isomerization to an azaenyne allene when treated with
tetrabutylammonium fluoride. In the presence of 1,4-cyclohexadiene, this azaenyne allene affords 6-phenyl-3-picoline and other products
corresponding to the trapping of an r,5-didehydro-3-picoline diradical.
The thermal cycloaromatization reactions of enediynes1 and
enyne allenes2 are of particular importance as a result of both
the involvement of these cyclizations in the DNA cleavage
mechanism of a large group of natural3 and designed4 cyto-
toxic compounds and the potential synthetic usefulness of
these cyclizations, particularly when coupled to free radical
cyclization cascades.5 An aza-variant of the cycloaromati-
zation of enediynes has been reported, which involves aza-
substitution of the internal ene double bond of the enediyne.
In this case heteroatom substitution has a profound impact
on facility of the cyclization and the nature and reactivity of
the intermediates involved.6,7All of the heteroatom-substituted
enyne allene analogues examined to date (Scheme 1) involve
heteroatom substitution on the allene or yne termini of the
system, including enyne ketenes8 (1, X ) CH, Y ) O), enyne
ketenimines9 (1, X ) N, Y ) CR′R′′), and enyne carbodi-
imides10 (1, X ) N, Y ) NR′), which undergo cyclizations
analogous to the Myers-Saito or Schmittel cyclizations of
enyne allenes (3a) to generate diradical or zwitterion
(6) (a) David, W. M.; Kerwin, S. M. J. Am. Chem. Soc. 1997, 119, 1464-
1465. (b) Feng, L.; Kumar, D.; Kerwin, S. M. J. Org. Chem. 2003, 68,
2234-2242. (c) Nadipuram, A. K.; David, W. M.; Kumar, D.; Kerwin, S.
M. Org. Lett. 2002, 4, 4543-4546.
(7) (a) Hoffner, J.; Schottelius, M. J.; Feichtinger, D.; Chen, P. J. Am.
Chem. Soc. 1998, 120, 376-385. (b) Kraka, E.; Cremer, D. J. Am. Chem.
Soc. 2000, 122, 8245-8264.
(8) (a) Foland, L. D.; Karlsson, J. O.; Perri, S. T.; Schwabe, R.; Xu, S.
L.; Patil, S.; Moore, H. W. J. Am. Chem. Soc. 1989, 111, 975-989. (b)
Tarli, A.; Wang, K. K. J. Org. Chem. 1997, 62, 8841-8847.
(9) (a) Shi, C. S.; Wang, K. K. J. Org. Chem. 1998, 63, 3517-3520. (b)
Schmittel, M.; Steffen, J.-P.; Angel, M. A. W.; Engels, B.; Lennartz, C.;
Hanrath, M. Angew. Chem., Int. Ed. 1998, 37, 1562-1564. (c) Alajarin,
M.; Vidal, A.; Ortin, M.-M. Tetrahedron Lett. 2003, 44, 3027-3030. (d)
Spo¨ler, C.; Engels, B. Chem. Eur. J. 2003, 9, 4670-4677.
(1) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660-
661.
(2) (a) Myers, A. G.; Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc. 1989,
111, 8057-8059. (b) Nagata, R.; Yamanaka, H.; Okazaki, E.; Saito, I.
Tetrahedron Lett. 1989, 30, 4995-4998. (c) Schmittel, M.; Kiau, S.; Siebert,
T.; Strittmatter, M. Tetrahedron Lett. 1996, 37, 7691-7694.
(3) Smith, A. L.; Nicolaou, K. C. J. Med. Chem. 1996, 39, 2103-17.
(4) Jones, G. B.; Fouad, F. S. Curr. Pharm. Des. 2002, 8, 2415-2440.
(5) (a) Grissom, J. W.; Gunawardena, G. U.; Klingberg, D.; Huang, D.
H. Tetrahedron 1996, 52, 6453-6518. (b) Li, H. B.; Zhang, H. R.; Petersen,
J. L.; Wang, K. K. J. Org. Chem. 2001, 66, 6662-6668. (c) Bowles, D.
M.; Palmer, G. J.; Landis, C. A.; Scott, J. L.; Anthony, J. E. Tetrahedron
2001, 57, 3753-3760.
10.1021/ol049266r CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/15/2004

stable than the corresponding skipped azaenediynes 2b,c by
12.0 and 7.3 kcal/mol, respectively, supporting the proposed
isomerization. There is only a small predicted energy dif-
ference between the less stable (Z)-imine isomers 3b,c and
the corresponding (E)-isomers (0.1 kcal/mol). Even for the
aldimines 3b,c (X ) N, R′ ) H), the (Z)-isomers required
for cyclization should be thermodynamically accessible, and
in the case of ketimines 3 (X ) N, R′ * H, e.g., 3d), the
reactive imine isomers (corresponding to (Z)-3b,c) should
predominate.
Scheme 1. Previously Reported Heteroenyne Allenes and
Azaenyne Allenes Derived from Skipped Azaenediynes
The results of (U)B3LYP/6-31G* calculations (Table 1)
indicate that the proposed aza-Myers-Saito cyclization of
azaenyne allene 3b has a slightly lower predicted barrier and
is slightly more exothermic than the Myers-Saito cyclization
of 3a. In both cases, the resulting singlet diradical 4••16 is
much lower in energy than the closed-shell singlet zwitterion
4(.17 A non-Cs-symmetric closed-shell singlet 5 lower in
energy than 4( was found for both the Myers-Saito case,
as had been previously noted by Squires18 and Carpenter,19
and the aza-Myers-Saito case.20 These results lead to the
prediction of a facile aza-Myers-Saito cyclization of aza-
enyne allenes that may afford products derived from both
diradical and ionic reaction pathways. The aza-Schmittel
cyclization of 3b is predicted to be much more facile than
the Schmittel cyclization of 3a, and although the aza-Myers-
Saito cyclization is predicted to be favored over aza-Schmittel
cyclization of 3b, the difference between the two pathways
is much smaller than in the enyne allene case.21 In accord
with previous computational studies of the Myers-Saito18,21-23
and Schmittel20,21,23 cyclizations, the transition states TS1b
and TS2b have little diradical character, indicating that
crossing to an open-shell surface occurs after these transition
states.
intermediates (Scheme 1), and 2,4,5-hexatrienenitriles,11
which do not undergo intramolecular thermal cyclization.
The ability of diradical-generating heteroenyne allenes to
participate in DNA cleavage chemistry12 or cascade cycliza-
tion reactions8,9,10,13 provides an impetus to study previously
unexplored members of this class of compounds.
The prototropic rearrangement of “skipped” azaenediynes
2b-d represents a potential route to C-alkynyl- N-allenyl
imines 3b-d, representatives of a class of azaenyne allenes
that have not yet been reported in the literature (Scheme 1).14
Here we report our computational and experimental studies
of the thermal rearrangements of azaenyne allenes 3b-d
derived from rearrangement of skipped azaenediynes
2b-d. We present evidence for an intermediate R,5-dide-
hydro-3-picoline diradical (4d••) derived from 3d and
computational studies that support the observed facility of
this aza-Myers-Saito cyclization and shed further light on
the effect of aza-substitution in this system.
(15) All calculations were carried out with the Guassian 98 package:
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; 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.; Rega, N.; Salvador,
P.; Dannenberg, J. J.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; 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.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M.
W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople,
J. A. Gaussian 98, Revision A.11.4; Gaussian, Inc.: Pittsburgh, PA, 2002.
(16) Despite a certain lack of theoretical rigor in applying UB3LYP
calculations to these open-shell singlets, we report these values for
comparison with the results in the enyne allene series in refs 2a, 18, and
19. One can reach the same conclusions by comparing the triplet diradical
energies.
(17) For the zwitterion 4a(, we find a structure lower in energy than
that reported in ref 19. We note that the wave function is unstable with
respect to symmetry breaking for both 4( and 5 at the B3LYP level.
(18) Wenthold, P. G.; Wierschke, S. G.; Nash, J. J.; Squires, R. R. J.
Am. Chem. Soc. 1994, 116, 7378-7392.
(19) Hughes, T. S.; Carpenter, B. K. J. Chem. Soc., Perkin Trans. 2 1999,
2291-2298.
(20) In the aza-Myers-Saito case, B3LYP/6-31G* calculations indicate
that 4b( is a saddle point corresponding to the transition state for the
interconversion of the two enantiomeric cyclic allenes 5b.
(21) Musch, P. W.; Remenyi, C.; Helten, H.; Engels, B. J. Am. Chem.
Soc. 2002, 124, 1823-1828.
Density functional calculations at the B3LYP/6-31G*
level15 demonstrate that the azaenyne allenes 3b,c are more
(10) (a) Lu, X.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2002, 67,
7797-7801. (b) Shi, C. S.; Zhang, Q.; Wang, K. K. J. Org. Chem. 1999,
64, 925-932. (c) Alajarin, M.; Molina, P.; Vidal, A. J. Nat. Prod. 1997,
60, 747-748.
(11) Gillmann, T.; Heckhoff, S. Tetrahedron Lett. 1996, 37, 839-840.
(12) Nakatani, K.; Maekawa, S.; Tanabe, K.; Saito, I. J. Am. Chem. Soc.
1995, 117, 10635-44.
(13) (a) Moore, H. W.; Yerxa, B. J. Chemtracts Org. Chem. 1992, 5,
273-313. (b) Schmittel, M.; Rodriguez, D.; Steffen, J.-P. Angew. Chem.,
Int. Ed. 2000, 39, 2152-2155.
(22) Cramer, C. J.; Kormos, B. L.; Seierstad, M.; Sherer, E. C.; Winget,
P. Org. Lett. 2001, 3, 1881-1884.
(23) Schreiner, P. R.; Prall, M. J. Am. Chem. Soc. 1999, 121, 8615-
8627.
(14) For theoretical studies of enyne allenes in which the central double
bond is replaced with various heteroatoms see: Bui, B. H.; Schreiner, P.
R. Org. Lett. 2003, 5, 4871-4874.
2060
Org. Lett., Vol. 6, No. 12, 2004

Table 1. Calculated Energies for Myers-Saito and Schmittel Cyclizations of 3a,ba
series
TS1
s4••b
t4••c
4(d
5
TS2
s6••b
t6••c
a
b
26.3e (23.3 ( 0.5)f
23.2e
-11.6 (-13.5 ( 4)g
-15.4
-10.2
-14.0
20.9
16.5e
0.1
-2.6
34.5e
27.7e
13.1
7.3
10.5
5.2
a (U)B3LYP/6-31G* energies with zero-point correction relative to the lowest energy, s-trans conformer of (Z)-3 in kcal/mol. b Open-shell singlet. c Triplet
diradical. d Closed-shell singlet with Cs-symmetry enforced. e One imaginary frequency. f Experimental data from ref 2a. g Experimental data from ref 18.
The skipped azaenediyne 7 was prepared by the condensa-
tion of 1-phenyl-3-(triisopropylsilyl)-propynone6b with excess
propargylamine in the presence of titanium(IV) ethoxide
(Scheme 2). When desilylation of 7 to 2d was carried out
which aldehyde 8 could be isolated (ca. 2% yield). Solutions
of 3d in 1,4-cyclohexadiene (1,4-chd) were allowed to stand
at 4 °C for 8 h (TLC monitoring) to afford a complex mixture
of products that included 6-phenyl-3-picoline 9 (20%) and
a mixture of cyclohexadiene adducts 10a,b (17%, ∼1:1 ratio),
which were characterized as the reduced product 11.
The formation of 8, 9, and 10a,b are all commensurate
with the intermediacy of the previously unreported R,5-
didehydro-3-picoline diradical 4d••. Rapid cyclization of 3d
to diradical 4d•• (compare Myers cyclization of 3a with t1/2
of 20.5 h at 39 °C),2a followed by hydrogen atom abstraction
from 1,4-chd affords a radical pair that can recombine to
give 10a,b or undergo subsequent hydrogen atom abstraction
to afford 9. Aldehyde 8 presumably arises from interception
of adventitious oxygen by diradical 4d••. Further support for
the intermediacy of 4d•• was obtained from analysis of
solutions of 3d in d8-THF, which afforded dideuterated 9.25
When solutions of 3d in methanol were stored at 0 °C,
5-methoxymethyl-2-phenylpyridine (12, 20%) was isolated.
A similar methanol addition product has been observed in
thermolyses of 3a, in methanol, and this has been attributed
to a partitioning between diradical and ionic reaction
pathways.2a,19 Despite the overall similarity in trapping
products from the thermal rearrangements of 3a and 3d, there
are differences between these two systems. In general, the
isolated yields of trapped products from 3d are lower than
those reported for 3a. It may be that a competing aza-
Schmittel pathway in the case of 3d leads to more complex
reaction mixtures and lower isolated yields. Also in contrast
to the case of 3a, which upon thermolysis in methanol gives
rise to mixtures of products derived from hydrogen atom
abstraction and methanol addition, we failed to isolate any
hydrogen atom abstraction product 9 from methanolic
solutions of 3d. This observation may be related to the
modest isolated yields of trapping products from reaction of
the diradical 4d•• with 1,4-chd. Perhaps 4d•• is less reactive
as a hydrogen atom abstraction agent toward 1,4-chd and
methanol when compared to 4a••. Alternatively, the meth-
oxymethyl pyridine 12 may arise from a different mechanism
involving methanol addition to the aminoallene functionality
of 3d, followed by cyclization of the resulting azadienyne.26
In conclusion, the formation of R,5-didehydro-3-picoline
diradical intermediates from skipped azaenediynes via isomer-
Scheme 2
by treatment with TBAF at -78 °C for 5 min, concomitant
isomerization occurred affording azaenyne allene 3d. Al-
though the instability of 3d prevented its chromatographic
purification, its structure was confirmed by NMR and MS
analysis of the reaction mixture after aqueous workup.24 The
1H NMR of 3d contains distinctive resonances for the allene
moiety: a methylene doublet at 5.36 ppm that couples with
a methine triplet at 7.60 ppm (J ) 6.0 Hz). The downfield
shift of the later is commensurate with the favored (E)-s-
trans conformation of 3d, in which the allene methine is
proximal to and in the deshielding region of the alkyne triple
bond. The 13C NMR spectra of 3d contains the expected
resonance for the allene sp carbon [212 ppm], and MS
analysis confirms the loss of the triisopropylsilyl group.
Solutions of azaenyne allene 3d in CDCl3 are unstable,
even when refrigerated, and afford complex mixtures from
(25) ) The 9 that was isolated (∼2% yield) consisted of ∼33%
1
(24) Data for 3d, isolated as a yellow oil: Rf 0.45 (ethyl acetate/hexanes,
dideuterated material by H NMR and MS analysis. Similarly low yields
1
1:9); H NMR (CDCl3) δ 3.82 (s, 1H), 5.36 (d, 2H, J ) 6.0 Hz), 7.38-
of 9 were obtained from reactions in THF, which is apparently a poor
7.41 (m, 3H), 7.60 (t, 1H, J ) 6.0 Hz), 8.07 (dd, 2H, J ) 7.6, 2.0 Hz); 13
C
hydrogen atom donor towards 4d••.
NMR (CDCl3) δ 75.35, 81.06, 89.72, 110.11, 127.99, 128.54, 131.12,
(26) We thank one of the reviewers for bringing this possibility to our
attention.
136.72, 147.10, 213.72; CIMS m/z 168 (MH+).
Org. Lett., Vol. 6, No. 12, 2004
2061

ization to azaenyne allenes and aza-Myers-Saito cyclization
has been predicted on the basis of DFT calculations. Skipped
azaenediynes are easily prepared, and their facile aza-Myers
cyclization provides a route to the previously unreported
picolinyl diradicals. In addition, the isomerization of skipped
azaenediynes and their subsequent rapid aza-Myers cycliza-
tion may have relevance to the recently reported DNA-
cleavage ability of cationic heterocyclic skipped azaene-
diynes.27 The potential modifications of azaenyne allenes
such as 3d by, for example, nitrogen atom protonation, are
of particular interest, and we are currently investigating the
potential of nitrogen atom protonation as a means to increase
the reactivity of the R,5-didehydro-3-picoline diradical, as
has been observed for the related aza-Bergman cyclization-
derived 2,5-didehydropyridine diradical.7
Acknowledgment. We thank Dr. Shuhua Ma from
University of Minnesota for helpful discussions. This work
was supported by grants from the Robert Welch Foundation
(F-1298) and the Petroleum Research Fund, administered by
the American Chemical Society (AC-34115).
Supporting Information Available: Coordinates and
energies of (U)B3LYP/6-31G* calculations and experimental
data for compounds 7, 3d, 8, 9, 10a,b, 11, and 12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(27) Tuntiwechapikul, W.; David, W. M.; Kumar, D.; Salazar, M.;
Kerwin, S. M. Biochemistry 2002, 41, 5283-5290.
OL049266R
2062
Org. Lett., Vol. 6, No. 12, 2004